Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia
Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia
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DOI：
10.3390/genes11060594
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发表时间：
2020-06-01
期刊：
影响因子：
3.5
通讯作者：
Uppugunduri, Chakradhara Rao Satyanarayana
中科院分区：
文献类型：
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作者：
Kodidela, Sunitha;Dorababu, Patchava;Uppugunduri, Chakradhara Rao Satyanarayana
影响急性淋巴细胞白血病（ALL）治疗中使用的化疗药物的药代动力学和/或药效学的遗传变异通常会导致治疗相关毒性（TRT）的发生。在这项研究中，我们探讨了候选基因变异与低剂量甲氨蝶呤和6-巯基嘌呤为基础的维持治疗（n = 73）的前100天内发生的早期血液学TRT（3 - 4级）的关联。采用实时荧光定量PCR等位基因识别法对ABCB 1、DHFR、GGH、FPGS、MTHFR、RFC 1、SLCO 1B1、TPMT和NUDT 15等14个候选基因进行基因分型。通过LC-MS/MS测量红细胞中的甲氨蝶呤聚谷氨酸盐（MTXPG 3 - 5）水平。在54.9%的患者中观察到早期血液学TRT（3 - 4级）。NUDT 15c.415 T等位基因与早期TRT发生相关[HR：3.04（95% CI：1.5 - 6.1）; p = 0.007]。通过检测FPG变异体（rs1544105 'T'）携带状态沿着NUDT 15 c.415 T等位基因，早期TRT预测的敏感性提高（从30.7%提高到89.7%）[HR = 2.7（1.5 - 4.7，p = 0.008）]。所有考虑的遗传变异均与MTXPG 3 - 5水平无关，MTXPG 3 - 5水平与早期TRT无关。NUDT 15c. 415 T等位基因携带状态可用作印度ALL患者的分层标记，以区分早期血液学TRT的高风险或低风险患者。
Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3-4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n= 73). Fourteen variants in the following candidate genes were genotyped using allele discrimination assay by real-time PCR:ABCB1,DHFR,GGH,FPGS,MTHFR,RFC1,SLCO1B1,TPMT, andNUDT15. Methotrexate polyglutamate (MTXPG3-5) levels in red blood cells were measured by LC-MS/MS. Early hematological TRT (grade 3-4) was seen in 54.9% of patients. TheNUDT15c.415T allele was associated with early TRT occurrence [HR: 3.04 (95% CI: 1.5-6.1);p= 0.007]. Sensitivity of early TRT prediction improved (from 30.7% to 89.7%) by consideringFPGSvariant (rs1544105'T') carrier status along withNUDT15c.415T allele [HR = 2.7 (1.5-4.7,p= 0.008)]. None of the considered genetic variants were associated with MTXPG3-5 levels, which in turn were not associated with early TRT.NUDT15c.415T allele carrier status could be used as a stratifying marker for Indian ALL patients to distinguish patients at high or low risk of developing early hematological TRT.