Baba Shahid M, Pandith Arshad A, Shah Zafar A, Geelani Sajad A, Mir Mohammad Muzaffar, Bhat Javid Rasool, Bhat Gul Mohammad
Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&K 190011 India.
Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&K India.
Indian J Hematol Blood Transfus. 2021 Jan;37(1):21-29. doi: 10.1007/s12288-020-01289-6. Epub 2020 May 26.
Inherited polymorphic sequence variations in drug transport genes like impact a portion of patients with hematologic malignancies that show intrinsic or acquire resistance to treatment. Keeping in view inter-individual sensitivities for such drugs, we through this case-control study tested whether C3435T and G2677T polymorphisms have any influence on the risk and treatment response in patients with chronic myeloid leukemia (CML) and B-acute lymphoblastic leukemia (B-ALL). Genotyping for polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism in 100 CML and 80 B-ALL patients along with 100 age and gender matched healthy controls. C3435T and G2677T polymorphism showed no association with CML. Genotype distribution revealed significant higher frequency of TT genotype for both SNPs in B-ALL cases and associated with increased B-ALL risk (OR 2.5, = 0.04 for 3435TT; OR 2.4, = 0.04 for 2677TT). There was no significant difference in genotype frequency of 3435C > T and 2677G > T among resistant and responsive groups for the two leukemia types. Kaplan-Meier survival plots revealed significantly lower event free survival in CML and B-ALL patients that were carriers of 3435TT genotype ( < 0.05). Multivariate analysis considered 3435TT genotype as independent risk factor for imatinib resistance in CML cases (HR 6.24, = 0.002) and increased relapse risk in B-ALL patients (HR 4.51, = 0.03). The current study provides preliminary evidence of a significant association between variant TT genotype and increased B-ALL risk. Also, results suggest that 3435TT genotype increases imatinib resistance in CML and influence therapeutic outcome in B-ALL.
药物转运基因中的遗传性多态性序列变异，例如，会影响一部分血液系统恶性肿瘤患者，这些患者表现出对治疗的内在或获得性耐药性。考虑到个体对这类药物的敏感性，我们通过这项病例对照研究，测试了C3435T和G2677T多态性是否对慢性粒细胞白血病（CML）和B淋巴细胞急性白血病（B-ALL）患者的风险和治疗反应有任何影响。通过聚合酶链反应-限制性片段长度多态性对100例CML患者、80例B-ALL患者以及100名年龄和性别匹配的健康对照进行多态性基因分型。C3435T和G2677T多态性与CML无关联。基因型分布显示，B-ALL病例中两种单核苷酸多态性（SNP）的TT基因型频率显著更高，且与B-ALL风险增加相关（3435TT的比值比为2.5，P = 0.04；对于2677TT，比值比为2.4，P = 0.04）。两种白血病类型的耐药组和敏感组之间，3435C>T和2677G>T的基因型频率没有显著差异。Kaplan-Meier生存曲线显示，CML和B-ALL患者中3435TT基因型携带者的无事件生存率显著较低（P<0.05）。多变量分析认为，3435TT基因型是CML病例中伊马替尼耐药的独立危险因素（风险比为6.24，P = 0.002），也是B-ALL患者复发风险增加的危险因素（风险比为4.51，P = 0.03）。本研究提供了初步证据，证明变异的TT基因型与B-ALL风险增加之间存在显著关联。此外，结果表明，3435TT基因型会增加CML患者对伊马替尼的耐药性，并影响B-ALL的治疗结果。
