Interaction between NUDT15 and ABCC4 variants enhances intolerability of 6-mercaptopurine in Japanese patients with childhood acute lymphoblastic leukemia
Interaction between NUDT15 and ABCC4 variants enhances intolerability of 6-mercaptopurine in Japanese patients with childhood acute lymphoblastic leukemia
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DOI：
10.1038/tpj.2017.12
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发表时间：
2018-03-01
影响因子：
2.8
通讯作者：
Manabe, A.
中科院分区：
文献类型：
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作者：
Tanaka, Y.;Nakadate, H.;Manabe, A.
6-巯基嘌呤(6-MP)是儿童急性淋巴细胞白血病(ALL)治疗的主要成分。一些候选基因变异与其毒性有关，但主要变异和联合变异的影响尚不清楚。我们使用COX回归分析来评估候选变异与95名日本患者6-MP不耐受累积发生率之间的时间相关性。多因素分析显示，严重白细胞减少的主要危险因素为ABCC4rs3765534、NUDT15rs116855232和rs186364861(P<；0.05)。NUDT15中间活性变异体，即杂合子rs116855232或rs186364861变异体，以及ABCC4 rs3765534变异体比单独的任何一个变异体表现出更多的白细胞减少。所有同时具有中间活性NUDT15变异和ABCC4 rs3765534变异的患者都出现了白细胞减少症，57.1%的患者在168天前需要50%的方案剂量。这些数据表明，NUDT15和ABCC4是6-MP不耐受的主要因素，这些变异体之间的相互作用增强了对6-MP的耐受。
6-Mercaptopurine (6-MP) is a main component of childhood acute lymphoblastic leukemia (ALL) treatment. Some candidate gene variants are associated with its toxicities, but the major variants and effects of combined variants remain unclear. We used Cox regression analysis to evaluate the time-dependent association between candidate variants and the cumulative incidence of 6-MP intolerability in 95 Japanese patients. The major risk factors for severe leukopenia were ABCC4 rs3765534, NUDT15 rs116855232 and rs186364861 in multi-covariate analysis (P < 0.05). NUDT15 intermediate activity variant, that is, heterozygous rs116855232 or rs186364861 variant, and the ABCC4 rs3765534 variant showed leukopenia more frequently than either variant alone. All patients with both the intermediate activity NUDT15 variant and the ABCC4 rs3765534 variant suffered from leukopenia, and 57.1% patients required 50% protocol dose by day 168. These data indicate that NUDT15 and ABCC4 are major factors for 6-MP intolerability and that the interaction between these variants enhances intolerability to 6-MP.