Lakkireddy Samyuktha, Aula Sangeetha, Avn Swamy, Kapley Atya, Rao Digumarti Raghunadha, Jamil Kaiser
Centre for Biotechnology and Bioinformatics, School of Life Sciences, Jawaharlal Nehru Institute of Advanced Studies (JNIAS), Secunderabad, Telangana, India ; Department of Biotechnology, Jawaharlal Nehru Technological Univesrity Anantapur (JNTUA), Ananthapuramu, Andhra Pradesh, India.
Department of Chemical Engineering, Jawaharlal Nehru Technological University Anantapur (JNTUA), Ananthapuramu, Andhra Pradesh, India.
Cell J. 2015 Fall;17(3):510-9. doi: 10.22074/cellj.2015.11. Epub 2015 Oct 7.
Cytochrome P450 is one of the major drug metabolizing enzyme families and its role in metabolism of cancer drugs cannot be less emphasized. The association be- tween single nucleotide polymorphisms (SNPs) in CYP1A1 and pathogenesis of chronic myeloid leukemia (CML) has been investigated in several studies, but the results observed vary based on varied risk factors. The objective of this study was to investigate the risk factors associated with the CYP1A1*2C [rs1048943: A>G] polymorphism in CML patients and its role in therapeutic response to imatinib mesylate (IM) affecting clinico-pathological parameters, in the Indian population.
In this case-control study, CYP1A12C was analysed in CML patients. After obtaining approval from the Ethics Committee of oncology hospital, we collected blood samples from 132 CML patients and 140 matched controls. Genom- ic DNA was extracted and all the samples were analysed for the presence of the CYP1A12C polymorphism using allele-specific polymerase chain reaction, and we examined the relationship of genotypes with risk factors such as gender, age, phase of the disease and other clinical parameters.
We observed a significant difference in the frequency distribution of CYP1A1*2C genotypes AA (38 vs. 16%, P=0.0001), AG (57 vs. 78%, P=0.0002) and GG (5 vs. 6%, P=0.6635) between patients and controls. In terms of response to IM therapy, significant variation was observed in the frequencies of AA vs AG in major (33 vs 67%) and poor (62 vs 31%) hematological responders, and AA vs AG in major (34 vs. 65%) and poor (78 vs. 22%) cytogenetic responders. However, the patients with the GG homozygous genotype did not show any significant therapeutic outcome.
The higher frequency of AG in controls indicates that AG may play a protec- tive role against developing CML. We also found that patients with the AG genotype showed favorable treatment response towards imatinib therapy, indicating that this polymorphism could serve as a good therapeutic marker in predicting response to such therapy.
细胞色素P450是主要的药物代谢酶家族之一，其在癌症药物代谢中的作用再怎么强调也不为过。多项研究对细胞色素P4501A1（CYP1A1）单核苷酸多态性（SNP）与慢性髓性白血病（CML）发病机制之间的关联进行了调查，但基于不同的风险因素，观察到的结果有所不同。本研究的目的是调查印度人群中CML患者与CYP1A1*2C[rs1048943：A>G]多态性相关的风险因素及其在甲磺酸伊马替尼（IM）治疗反应中对临床病理参数的影响。
在这项病例对照研究中，对CML患者的CYP1A12C进行了分析。获得肿瘤医院伦理委员会批准后，我们收集了132例CML患者和140例匹配对照的血样。提取基因组DNA，使用等位基因特异性聚合酶链反应分析所有样本中CYP1A12C多态性的存在情况，并研究基因型与性别、年龄、疾病分期和其他临床参数等风险因素之间的关系。
我们观察到患者和对照之间CYP1A1*2C基因型AA（38%对16%，P=0.0001）、AG（57%对78%，P=0.0002）和GG（5%对6%，P=0.6635）的频率分布存在显著差异。在IM治疗反应方面，主要血液学反应者（33%对67%）和较差血液学反应者（62%对31%）中AA与AG的频率，以及主要细胞遗传学反应者（34%对65%）和较差细胞遗传学反应者（78%对22%）中AA与AG的频率存在显著差异。然而，GG纯合基因型的患者未显示出任何显著的治疗效果。
对照中AG的较高频率表明AG可能对CML的发生具有保护作用。我们还发现，AG基因型的患者对伊马替尼治疗表现出良好的治疗反应，表明这种多态性可作为预测此类治疗反应的良好治疗标志物。
