Laboratory of Oncobiology and Hematology (LOH), University Clinic of Hematology, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal.
Coimbra Institute for Clinical and Biomedical Research (iCBR)-Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal.
Int J Mol Sci. 2022 Aug 29;23(17):9815. doi: 10.3390/ijms23179815.
Solute carrier (SLC) and ATP-binding cassette (ABC) transporters comprise a variety of proteins expressed on cell membranes responsible for intrusion or extrusion of substrates, respectively, including nutrients, xenobiotics, and chemotherapeutic agents. These transporters mediate the cellular disposition of tyrosine kinase inhibitors (TKIs), and their genetic variants could affect its function, potentially predisposing patients to chronic myeloid leukaemia (CML) and modulating treatment response. We explored the impact of genetic variability (single nucleotide variants-SNVs) of drug transporter genes (, , , and ) on CML susceptibility, drug response, and mutation status. We genotyped 10 SNVs by tetra-primers-AMRS-PCR in 198 CML patients and 404 controls, and assessed their role in CML susceptibility and prognosis. We identified five SNVs associated with CML predisposition, with some variants increasing disease risk, including TT genotype (rs1045642), and others showing a protective effect (GG genotype rs274558). We also observed different haplotypes and genotypic profiles associated with CML predisposition. Relating to drug response impact, we found that CML patients with the CC genotype (rs2231142 ) had an increased risk of TKI resistance (six-fold). Additionally, CML patients carrying the CG genotype (rs683369 ) presented a 4.54-fold higher risk of mutations. Our results suggest that drug transporters' SNVs might be involved in CML susceptibility and TKI response, and predict the risk of mutations, highlighting the impact that SNVs could have in therapeutic selection.
溶质载体 (SLC) 和 ATP 结合盒 (ABC) 转运蛋白包含多种表达在细胞膜上的蛋白质，分别负责底物的内吞或外排，包括营养物质、外源性化学物质和化疗药物。这些转运蛋白介导酪氨酸激酶抑制剂 (TKI) 的细胞处置，其遗传变异可能影响其功能，使患者易患慢性髓性白血病 (CML) 并调节治疗反应。我们探讨了药物转运体基因 (、、、和 ) 的遗传变异（单核苷酸变异-SNVs）对 CML 易感性、药物反应和 突变状态的影响。我们通过四引物-AMRS-PCR 在 198 例 CML 患者和 404 例对照中对 10 个 SNV 进行基因分型，并评估它们在 CML 易感性和预后中的作用。我们确定了与 CML 易感性相关的五个 SNVs，其中一些变体增加了疾病风险，包括 TT 基因型 (rs1045642)，而其他变体则表现出保护作用（GG 基因型 rs274558）。我们还观察到与 CML 易感性相关的不同单倍型和基因型谱。关于药物反应的影响，我们发现 CML 患者的 CC 基因型 (rs2231142 ) 发生 TKI 耐药的风险增加（六倍）。此外，携带 CG 基因型 (rs683369 ) 的 CML 患者发生 突变的风险增加了 4.54 倍。我们的结果表明，药物转运体的 SNVs 可能参与 CML 易感性和 TKI 反应，并预测 突变的风险，突出了 SNVs 在治疗选择中的影响。
