Screening of Novel Pharmacogenetic Candidates for Mercaptopurine-Induced Toxicity in Patients With Acute Lymphoblastic Leukemia
Screening of Novel Pharmacogenetic Candidates for Mercaptopurine-Induced Toxicity in Patients With Acute Lymphoblastic Leukemia
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筛选针对急性淋巴细胞白血病患者的巯嘌呤引起的毒性的新型药物遗传学候选药物
DOI：
10.3389/fphar.2020.00267
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发表时间：
2020-03-20
影响因子：
5.6
通讯作者：
Lu, Xiaoxi
中科院分区：
文献类型：
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作者：
Cao, Minyuan;Yin, Dandan;Lu, Xiaoxi
一小部分急性淋巴细胞白血病（ALL）患者在使用6 - 巯基嘌呤（6MP）治疗后可能会出现严重的白细胞减少症，这在很大程度上可由TPMT和NUDT15的胚系变异来解释。然而，少数出现此类药物不良反应的患者具有NUDT15（野生型/野生型）TPMT（野生型/野生型）基因型，这表明可能有其他遗传因素参与其中。在这项研究中，我们对173例儿童ALL患者中参与药物代谢I/II期的基因中的539个外显子非同义药物遗传变异进行了基因分型，并对6MP诱导的白细胞减少症进行了关联筛选。除了NUDT15（rs116855232，P = 6.4×10⁻¹¹）和TPMT（rs1142345，P = 0.003）外，在CYP2A7基因中还发现了一个新的变异（即rs73032311，P = 0.0007），它独立于NUDT15/TPMT变异。此外，COMT中的一个变异（即rs4680）与6MP诱导的肝毒性显著相关（P = 0.007）。总之，CYP2A7和COMT中的变异可被视为6MP诱导毒性的新的潜在药物遗传标记，但还需要更大样本量的独立验证以及对相关机制的研究。
A small proportion of patients with acute lymphoblastic leukemia (ALL) may experience severe leukopenia after treating with 6-mercaptopurine (6MP), which can be largely explained by germline variants in TPMT and NUDT15. However, a minority of patients who suffered such adverse drug reaction have NUDT15(wt/wt)TPMT(wt/wt) genotype, indicating that other genetic factors may take part in. In this study, we genotyped 539 exon-located nonsilent pharmacogenetic variants in genes involved in phase I/II of drug metabolism in 173 pediatric patients with ALL and conducted association screening for 6MP-induced leukopenia. Besides NUDT15 (rs116855232, P = 6.4 x 10(-11)) and TPMT (rs1142345, P = 0.003), a novel variant was identified in CYP2A7 gene (i.e., rs73032311, P = 0.0007), which is independent of NUDT15/TPMT variant. In addition, a variant (i.e., rs4680) in COMT is significantly associated with 6MP-induced hepatotoxicity (P = 0.007). In conclusion, variants in CYP2A7 and COMT may be considered as novel potential pharmacogenetic markers for 6MP-induced toxicities, but additional independent validations with large sample size and investigations on related mechanisms are further needed.