Inherited NUDT15 Variant Is a Genetic Determinant of Mercaptopurine Intolerance in Children With Acute Lymphoblastic Leukemia
Inherited NUDT15 Variant Is a Genetic Determinant of Mercaptopurine Intolerance in Children With Acute Lymphoblastic Leukemia
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DOI：
10.1200/jco.2014.59.4671
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发表时间：
2015-04-10
影响因子：
45.3
通讯作者：
Relling, Mary V.
中科院分区：
文献类型：
--
作者：
Yang, Jun J.;Landier, Wendy;Relling, Mary V.
巯基嘌呤（MP）是治疗急性淋巴细胞白血病（ALL）的主要药物。我们进行了全基因组关联研究（GWAS），以全面确定MP不耐受的遗传基础，在儿童ALL.Patients and MethodsThe发现GWAS和复制队列包括657和371名儿童从两个前瞻性临床试验。MP剂量强度是药物耐受性和毒性的标志物，并被定义为规定的剂量除以计划的协议剂量维持治疗期间，其与基因型进行了评估，使用线性混合效应model.ResultsMP剂量强度不同的种族和民族，与东亚遗传血统呈负相关（P < .001）。GWAS揭示了两个与剂量强度相关的全基因组显著位点：TPMT中的rs 1142345（Tyr 240 Cys，存在于 *3A和 *3C变体中; P = 8.6 x 10（-9））和NUDT 15中的rs 116855232（P = 8.8 x 10（-9）），具有独立复制。rs 116855232位点TT基因型患者对MP敏感，平均剂量强度为8.3%，而TC和CC基因型患者分别耐受计划剂量的63%和83.5%。NUDT 15变异在东亚人和西班牙裔人中最常见，在欧洲人中罕见，在非洲人中未观察到，这导致了MP耐受性的祖先相关差异。儿童纯合子的TPMT或NUDT 15变异或杂合子两者，100%需要50%的MP剂量减少，相比之下，只有7.7%other.ConclusionWe描述的NUDT 15的种系变异与MP不耐受儿童ALL，这可能有影响，在这种疾病的治疗个性化。(C)2015年美国临床肿瘤学会
PurposeMercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL.Patients and MethodsThe discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model.ResultsMP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 x 10(-9)) and rs116855232 in NUDT15 (P = 8.8 x 10(-9)), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required 50% MP dose reduction, compared with only 7.7% of others.ConclusionWe describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease. (C) 2015 by American Society of Clinical Oncology