Harivenkatesh Natarajan, Kumar Lalit, Bakhshi Sameer, Sharma Atul, Kabra Madhulika, Velpandian Thirumurthy, Gogia Ajay, Shastri Shivaram S, Gupta Yogendra Kumar
a Department of Pharmacology , All India Institute of Medical Sciences , New Delhi , India.
b Medical Oncology , All India Institute of Medical Sciences , New Delhi , India.
Leuk Lymphoma. 2017 Sep;58(9):1-9. doi: 10.1080/10428194.2017.1287359. Epub 2017 Apr 3.
Influence of polymorphisms in the genes coding for imatinib transporters and metabolizing enzymes on cytogenetic relapse in patients with chronic myeloid leukemia (CML) is not known. One hundred and four patients (52 cases with cytogenetic relapse and 52 controls without relapse) with chronic-phase CML on imatinib therapy and have completed 5 years of follow-up were enrolled. The following single nucleotide polymorphisms (SNPs) were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene, using PCR-RFLP method and validated by direct gene sequencing. Imatinib trough levels were measured using LC-MS/MS. Patients with CC genotype for MDR1-C1236T polymorphism were at significantly higher risk for cytogenetic relapse [OR =4.382, 95% CI (1.145, 16.774), p = .022], while those with TT genotype for MDR1-C3435T polymorphism had significantly lower risk of relapse [OR =0.309, 95% CI (0.134, 0.708), p = .005]. Imatinib trough levels were lower in patients with relapse compared to those without relapse (1551.4 ± 1324.1 vs. 2154.2 ± 1358.3 ng/mL; p = .041). MDR1-C3435T genotype [adjusted-OR: 0.266; 95% CI (0.111, 0.636); p = .003] and trough levels (p = .014) were independent predictors of relapse in multivariate analysis. To conclude, C1236T and C3435T polymorphisms in MDR1 gene and trough levels significantly influence the risk of cytogenetic relapse. MDR1-C3435T genotype might emerge as a potential biomarker to predict the risk of cytogenetic relapse in patients with CML.
伊马替尼转运蛋白和代谢酶编码基因多态性对慢性髓性白血病（CML）患者细胞遗传学复发的影响尚不清楚。本研究纳入了104例接受伊马替尼治疗且已完成5年随访的慢性期CML患者（52例发生细胞遗传学复发，52例未复发作为对照）。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法对多药耐药蛋白1（MDR1）基因中的C1236T、C3435T、G2677T/A以及细胞色素P450 3A5（CYP3A5）基因中的A6986G等单核苷酸多态性（SNP）进行基因分型，并通过直接基因测序进行验证。使用液相色谱-串联质谱法（LC-MS/MS）测定伊马替尼谷浓度。MDR1基因C1236T多态性为CC基因型的患者发生细胞遗传学复发的风险显著更高[比值比（OR）=4.382，95%置信区间（CI）（1.145，16.774），p = 0.022]，而MDR1基因C3435T多态性为TT基因型的患者复发风险显著更低[OR =0.309，95%CI（0.134，0.708），p = 0.005]。复发患者的伊马替尼谷浓度低于未复发患者（1551.4±1324.1 vs. 2154.2±1358.3 ng/mL；p = 0.
