Yang Jun J, Landier Wendy, Yang Wenjian, Liu Chengcheng, Hageman Lindsey, Cheng Cheng, Pei Deqing, Chen Yanjun, Crews Kristine R, Kornegay Nancy, Wong F Lennie, Evans William E, Pui Ching-Hon, Bhatia Smita, Relling Mary V
Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.
J Clin Oncol. 2015 Apr 10;33(11):1235-42. doi: 10.1200/JCO.2014.59.4671. Epub 2015 Jan 26.
Mercaptopurine (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.
The 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.
MP 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 × 10(-9)) and rs116855232 in NUDT15 (P = 8.8 × 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.
We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.
巯嘌呤（MP）是急性淋巴细胞白血病（ALL）根治性治疗的主要药物。我们进行了一项全基因组关联研究（GWAS），以全面确定ALL患儿MP不耐受的遗传基础。
发现GWAS和复制队列包括来自两项前瞻性临床试验的657名和371名儿童。MP剂量强度是药物耐受性和毒性的一个指标，定义为维持治疗期间规定剂量除以计划方案剂量；使用线性混合效应模型评估其与基因型的关联。
MP剂量强度因种族和民族而异，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rs1142345（Tyr240Cys，存在于3A和3C变体中；P = 8.6×10^(-9)）和NUDT15中的rs116855232（P = 8.8×10^(-9)），并得到独立验证。rs116855232位点TT基因型的患者对MP极其敏感，平均剂量强度为8.3%，而TC和CC基因型的患者分别耐受计划剂量的63%和83.5%。NUDT15变体在东亚人和西班牙裔中最常见，在欧洲人中罕见，在非洲人中未观察到，这导致了MP耐受性的种族相关差异。对于TPMT或NUDT15变体纯合或两者杂合的儿童，100%需要将MP剂量降低≥50%，而其他儿童中这一比例仅为7.7%。
我们描述了一种NUDT15种系变体，它与儿童ALL中的MP不耐受密切相关，这可能对该疾病的个体化治疗具有重要意义。
