Online first
Original research article
Published online: 2025-03-31
Evaluation of polymorphism in BCL-2, PD-1, and PD-L1 genes in myelodysplastic neoplasms
1
, 2, 2, 2, 1, 1
, 2, 2, 2, 1, 1
DOI: 10.5603/ahp.104373
Abstract
BCL-2 family proteins regulate apoptosis, while programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) act as negative regulators of the immune system. An association has been found between abnormalities in B-cell CLL/lymphoma 2 (BCL-2) and PD-1/PD-L1 proteins and susceptibility to myelodysplastic neoplasms. The aim of this study was to assess polymorphisms in genes encoding BCL-2, PD-1, and PD-L1, and their impact on the clinical course of myelodysplastic neoplasms (MDS), treatment effectiveness, and correlation with other prognostic factors in MDS. The study included 50 individuals with a median age of 70 diagnosed with MDS. Genotyping for BCL2 (rs1564483, rs2279115), CD274 (rs2297136, rs4143815), and PDCD1 (rs10204525, rs2227981) was performed using LightSNiP assays. Real-time PCR reactions were conducted on a LightCycler 480 II device. Mann-Whitney U test and Fisher’s exact test were employed for analysis. Kaplan-Meier curves and the log-rank test were used for survival analysis. The analysis revealed that the BCL2 rs1564483 G allele is associated with better overall survival compared to patients with the BCL2 rs1564483 AA genotype (p=0.037) and is more common in patients who achieved complete remission (CR) or partial remission (PR) after first-line treatment (regardless of the therapy used) (p=0.021).
Keywords: PD-1/PD-L1BCL-2MDSpolymorphism
References
- Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 2020; 17(7): 395–417.
- Campbell KJ, Tait SWG. Targeting BCL-2 regulated apoptosis in cancer. Open Biol. 2018; 8(5).
- Kuszczak B, Wróbel T, Wicherska-Pawłowska K, et al. The Role of BCL-2 and PD-1/PD-L1 Pathway in Pathogenesis of Myelodysplastic Syndromes. Int J Mol Sci. 2023; 24(5).
- Buja LM. The cell theory and cellular pathology: Discovery, refinements and applications fundamental to advances in biology and medicine. Exp Mol Pathol. 2021; 121: 104660.
- Peng X, Shi J, Sun W, et al. Genetic polymorphisms of IL-6 promoter in cancer susceptibility and prognosis: a meta-analysis. Oncotarget. 2018; 9(15): 12351–12364.
- Zhang X, Weng W, Xu W, et al. Role of Bcl-2 -938 C>A polymorphism in susceptibility and prognosis of cancer: a meta-analysis. Sci Rep. 2014; 4: 7241.
- Okazaki T, Maeda A, Nishimura H, et al. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A. 2001; 98(24): 13866–13871.
- Salmaninejad A, Khoramshahi V, Azani A, et al. PD-1 and cancer: molecular mechanisms and polymorphisms. Immunogenetics. 2018; 70(2): 73–86.
- Hashemi M, Karami S, Sarabandi S, et al. Association between and Polymorphisms and the Risk of Cancer: A Meta-Analysis of Case-Control Studies. Cancers (Basel). 2019; 11(8).
- Mądry K, Machowicz R, Waszczuk-Gajda A, et al. Demographic, Hematologic, and Clinical Features of Myelodysplastic Syndrome Patients: Results from the First Polish Myelodysplastic Syndrome Registry. Acta Haematol. 2015; 134(2): 125–134.
- Zeidan AM, Shallis RM, Wang R, et al. Epidemiology of myelodysplastic syndromes: Why characterizing the beast is a prerequisite to taming it. Blood Rev. 2019; 34: 1–15.
- Papaemmanuil E, Gerstung M, Malcovati L, et al. Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013; 122(22): 3616–27; quiz 3699.
- Mądry K, Drozd-Sokołowska J, Lis K, et al. Diagnosis of myelodysplastic syndromes in Poland: Polish Adult Leukemia Group (PALG) 2021 recommendations. Acta Haematologica Polonica. 2022; 53(1): 3–18.
- Zeidan AM, Platzbecker U, Bewersdorf JP, et al. Consensus proposal for revised International Working Group 2023 response criteria for higher-risk myelodysplastic syndromes. Blood. 2023; 141(17): 2047–2061.
- Majcherek M, Kiernicka-Parulska J, Mierzwa A, et al. The diagnostic and prognostic significance of flow cytometric bone marrow assessment in myelodysplastic syndromes according to the European LeukemiaNet recommendations in single-centre real-life experience. Scand J Immunol. 2021; 94(2): e13028.
- Zhang Y, Wu J, Qin T, et al. Comparison of the revised 4th (2016) and 5th (2022) editions of the World Health Organization classification of myelodysplastic neoplasms. Leukemia. 2022; 36(12): 2875–2882.
- Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012; 120(12): 2454–2465.
- Visconte V, Tiu RV, Rogers HJ. Pathogenesis of myelodysplastic syndromes: an overview of molecular and non-molecular aspects of the disease. Blood Res. 2014; 49(4): 216–227.
- Mądry K, Budziszewska B, Lis K, et al. Treatment recommendations developed by MDS experts of the Polish Adult Leukemia Group (PALG) for management of myelodysplastic syndromes (MDSs) and other MDS-related conditions in Poland for 2021. Acta Haematologica Polonica. 2022; 53(2): 75–93.
- Calvi LM, Li AJ, Becker MW. What is the role of the microenvironment in MDS? Best Pract Res Clin Haematol. 2019; 32(4): 101113.
- Boudard D, Vasselon C, Berthéas MF, et al. Expression and prognostic significance of Bcl-2 family proteins in myelodysplastic syndromes. Am J Hematol. 2002; 70(2): 115–125.
- Mittelman M, Oster HS, Hoffman M, et al. The lower risk MDS patient at risk of rapid progression. Leuk Res. 2010; 34(12): 1551–1555.
- Vidal V, Ginet C, Karsenti J, et al. BCL2L10 Quantification Is a Predictive Factor of Response to Azacitidine in Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML). Blood. 2014; 124(21): 3261–3261.
- Xu Z, Taylor JA. SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucleic Acids Res. 2009; 37(Web Server issue): W600–W605.
- Azadeh Jouneghani M, Keshavarzi F, Haghnazari N, et al. The Investigation of the Association Between the 3'-UTR rs1564483 Polymorphism and miR-296-3p in the Development of Breast and Gastric Cancers. Clin Med Insights Oncol. 2023; 17: 11795549231207835.
- Chen Xi, Song Y, Tian Y, et al. miR-149-3p Enhances Drug Sensitivity of AML Cells by Inhibiting Warburg Effect Through PI3K/AKT Pathway. Cell Biochem Biophys. 2024; 82(4): 3287–3296.
- Pan W, Yang J, Wei J, et al. Functional BCL-2 regulatory genetic variants contribute to susceptibility of esophageal squamous cell carcinoma. Sci Rep. 2015; 5: 11833.
- Yang X, Gao F, Ma F, et al. Association of the functional BCL-2 rs2279115 genetic variant and small cell lung cancer. Tumour Biol. 2016; 37(2): 1693–1698.
- Renner W, Langsenlehner U, Krenn-Pilko S, et al. BCL2 genotypes and prostate cancer survival. Strahlenther Onkol. 2017; 193(6): 466–471.
- Kaderi MA, Norberg M, Murray F, et al. The BCL-2 promoter (-938C>A) polymorphism does not predict clinical outcome in chronic lymphocytic leukemia. Leukemia. 2008; 22(2): 339–343.
- Bhushann Meka P, Jarjapu S, Vishwakarma SK, et al. Influence of BCL2-938 C>A promoter polymorphism and BCL2 gene expression on the progression of breast cancer. Tumour Biol. 2016; 37(5): 6905–6912.
- Seto M, Jaeger U, Hockett RD, et al. Alternative promoters and exons, somatic mutation and deregulation of the Bcl-2-Ig fusion gene in lymphoma. EMBO J. 1988; 7(1): 123–131.
- Masago K, Togashi Y, Fujita S, et al. Effect of the BCL2 gene polymorphism on survival in advanced-stage non-small cell lung cancer patients who received chemotherapy. Oncology. 2013; 84(4): 214–218.
- Hirata H, Hinoda Y, Nakajima K, et al. The bcl2 -938CC genotype has poor prognosis and lower survival in renal cancer. J Urol. 2009; 182(2): 721–727.
- Hirata H, Hinoda Y, Nakajima K, et al. The bcl2 -938CC genotype has poor prognosis and lower survival in renal cancer. J Urol. 2009; 182(2): 721–727.
- Bieliński K, Puła B, Bołkun Ł. Checkpoint inhibitors as potential therapeutics in acute myeloid leukemia. Acta Haematol Pol. 2024; 55(6): 343–353.
- Kondo A, Yamashita T, Tamura H, et al. Interferon-gamma and tumor necrosis factor-alpha induce an immunoinhibitory molecule, B7-H1, via nuclear factor-kappaB activation in blasts in myelodysplastic syndromes. Blood. 2010; 116(7): 1124–1131.
- Wang W, Li F, Mao Y, 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): 641–648.
- Lee SY, Jung DK, Choi JE, et al. Functional polymorphisms in PD-L1 gene are associated with the prognosis of patients with early stage non-small cell lung cancer. Gene. 2017; 599: 28–35.
- Ohhara Y, Tomaru U, Kinoshita I, et al. Polymorphisms of the PD-L1 gene 3'-untranslated region are associated with the expression of PD-L1 in non-small cell lung cancer. Genes Chromosomes Cancer. 2024; 63(1): e23216.
- Tan D, Sheng Li, Yi QH. Correlation of PD-1/PD-L1 polymorphisms and expressions with clinicopathologic features and prognosis of ovarian cancer. Cancer Biomark. 2018; 21(2): 287–297.
- Sallman DA, McLemore AF, Aldrich AL, et al. TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype. Blood. 2020; 136(24): 2812–2823.
- Tcvetkov N, Morozova E, Epifanovskaya O, et al. Profile of Checkpoint Molecules Expression on Bone Marrow Cell Populations in Patients with High-Risk Myelodysplastic Syndrome. Blood. 2020; 136(Supplement 1): 43–44.