Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia.
Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia.
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DOI：
10.1001/jama.2015.0894
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发表时间：
2015-02-24
影响因子：
120.7
通讯作者：
Evans, William E.
中科院分区：
文献类型：
--
作者：
Diouf, Barthelemy;Crews, Kristine R.;Lew, Glen;Pei, Deqing;Cheng, Cheng;Bao, Ju;Zheng, Jie J.;Yang, Wenjian;Fan, Yiping;Wheeler, Heather E.;Wing, Claudia;Delaney, Shannon M.;Komatsu, Masaaki;Paugh, Steven W.;McCorkle, Joseph Robert;Lu, Xiaomin;Winick, Naomi J.;Carroll, William L.;Loh, Mignon L.;Hunger, Stephen P.;Devidas, Meenakshi;Pui, Ching-Hon;Dolan, M. Eileen;Relling, Mary V.;Evans, William E.
随着儿童急性淋巴细胞白血病（ALL）的治愈率超过85%，迫切需要减轻可能影响生活质量的治疗毒性。周围神经病变是微管抑制剂长春新碱的主要剂量限制性毒性，长春新碱是一种用于所有ALL儿童的抗癌药物。确定与ALL儿童中长春新碱诱导的周围神经病变的发生或严重程度相关的遗传种系变异。所有患者均已入组两项针对儿童ALL的前瞻性临床试验之一，其中包括36-39剂长春新碱治疗。在所有有DNA样本的患者中进行全基因组单核苷酸多态性（SNP）分析和长春新碱诱导的周围神经病变评估（n=321例患者）; 222例患者（中位年龄为6.0岁，范围0.1-18.8岁），1994-1998年根据圣犹达儿童研究医院方案入组（St. Jude队列），毒性随访至2001年1月，2007-2010年间，99名患者（中位年龄11.4岁，范围3.0-23.8岁）按照儿童肿瘤学小组方案AALL 0433（COG队列）入组，毒性随访至2011年5月。使用人白血病细胞和诱导多能干细胞神经元来评估较低的CEP 72表达对长春新碱敏感性的影响。长春新碱治疗，剂量为1.5或2.0 mg/m2，作为儿童ALL方案导向化疗的组成部分。在每次临床访视时，使用美国国家癌症研究所不良事件通用术语标准评估了阿贝斯汀诱导的周围神经病变，并将其前瞻性分级为轻度（1级）、中度（2级）、严重/致残（3级）或危及生命（4级）。St. Jude队列中28.8%的患者（n=64/222）和COG队列中22.2%的患者（n=22/99）在继续治疗期间发生2-4级长春新碱诱导的神经病变。CEP 72基因启动子区的SNP（编码参与微管形成的中心体蛋白）与长春新碱神经病变显著相关（Meta p =6.3 × 10−9）。该SNP的次要等位基因频率为37%（235/642），321例患者中有50例（16%，95% CI 11.6%-19.5%）为风险等位基因（rs 924607处的TT）纯合子。在具有高风险CEP 72基因型的患者中，（rs 924607处TT），50例患者中的28例（56%，95% CI 41.2-70.0）至少发生一次2-4级神经病变，发生率高于CEP 72 CC或CT基因型患者（271例患者中的58例; 21.4%，95% CI 16.9-26.7）; p=2.4×10−6。神经病变的严重程度（等级）（泊松回归为2.4倍（p<0.0001），基于神经病变的平均等级为2.7倍（1.23 [95% CI 0.74 - 1.72]对比0.45 [95% CI 0.3 - 0.6]; t检验p=0.004））。CEP 72启动子SNP显示为转录抑制因子创建结合位点，导致mRNA表达降低，并且降低人神经元和白血病细胞中的CEP 72表达增加了其对长春新碱的敏感性。在这项对ALL儿童的初步研究中，CEP 72启动子区的遗传多态性与长春新碱相关周围神经病变的风险和严重程度增加相关。如果在其他人群中重复，这一发现可能为这种广泛处方的抗癌药物的安全给药提供依据。
With cure rates of childhood acute lymphoblastic leukemia (ALL) exceeding 85%, there is compelling need to mitigate treatment toxicities that can compromise quality of life. Peripheral neuropathy is the major dose-limiting toxicity of the microtubule inhibitor vincristine, an anticancer agent given to every child with ALL. Identify genetic germline variants associated with the occurrence or severity of vincristine-induced peripheral neuropathy in children with ALL. All patients had been enrolled in one of two prospective clinical trials for childhood ALL that included treatment with 36–39 doses of vincristine. Genome-wide single nucleotide polymorphism (SNP) analysis and vincristine-induced peripheral neuropathy were assessed in all patients from whom DNA was available (n=321 patients); 222 patients (median age at 6.0 years, range 0.1–18.8 years) enrolled between 1994–1998 on the St. Jude Children’s Research Hospital protocol Total XIIIB (St. Jude cohort) with toxicity followed through January 2001, and 99 patients (median age 11.4 years, range 3.0–23.8 years) enrolled between 2007–2010 on the Children’s Oncology Group protocol AALL0433 (COG cohort) with toxicity followed through May 2011. Human leukemia cells and induced pluripotent stem cell neurons were used to assess the effects of lower CEP72 expression on vincristine sensitivity. Treatment with vincristine at a dosage of 1.5 or 2.0 mg/m2 as a component of protocol directed chemotherapy for childhood ALL. Vincristine-induced peripheral neuropathy was assessed at each clinic visit using the National Cancer Institute Common Terminology Criteria for Adverse Events and prospectively graded as mild (grade 1), moderate (grade 2), serious/disabling (grade 3), or life-threatening (grade 4). Grade 2–4 vincristine-induced neuropathy during continuation therapy occurred in 28.8% of patients (n=64 of 222) in the St. Jude cohort and in 22.2% of patients (n=22 of 99) in the COG cohort. A SNP in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, had a significant association with vincristine neuropathy (meta p =6.3 × 10−9). This SNP had a minor allele frequency of 37% (235/642), with 50 of 321 patients (16%, 95% CI 11.6%–19.5%) homozygous for the risk allele (TT at rs924607). Among patients with the high-risk CEP72 genotype (TT at rs924607), 28 of 50 patients (56%, 95% CI 41.2–70.0) developed at least one episode of grade 2–4 neuropathy, a higher rate than in patients with the CEP72 CC or CT genotype (58 of 271 patients; 21.4%, 95% CI 16.9–26.7); p=2.4×10−6. The severity (grade) of neuropathy was greater (2.4-fold by Poisson regression (p<0.0001), 2.7-fold based on mean grade of neuropathy (1.23 [95% CI 0.74 – 1.72] versus 0.45 [95% CI 0.3 – 0.6]; t test p=0.004)) in patients homozygous for the CEP72 risk allele (TT genotype), compared to patients with the CC or CT genotype. The CEP72 promoter SNP was shown to create a binding site for a transcriptional repressor causing lower mRNA expression, and reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine. In this preliminary study of children with ALL, an inherited polymorphism in the promoter region of CEP72 was associated with increased risk and severity of vincristine-related peripheral neuropathy. If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent.
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DOI：
10.1056/nejmoa0900386
发表时间：
2009-06-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Pui CH;Campana D;Pei D;Bowman WP;Sandlund JT;Kaste SC;Ribeiro RC;Rubnitz JE;Raimondi SC;Onciu M;Coustan-Smith E;Kun LE;Jeha S;Cheng C;Howard SC;Simmons V;Bayles A;Metzger ML;Boyett JM;Leung W;Handgretinger R;Downing JR;Evans WE;Relling MV
通讯作者：
Relling MV
影响因子：
3
作者：
Gidding, CEM;Meeuwsen-de Boer, GJ;de Graaf, SSN
通讯作者：
de Graaf, SSN
影响因子：
2.1
作者：
Li, Yun;Willer, Cristen J.;Ding, Jun;Scheet, Paul;Abecasis, Goncalo R.
通讯作者：
Abecasis, Goncalo R.
影响因子：
5.1
作者：
CROM, WR;DEGRAAF, SSN;EVANS, WE
通讯作者：
EVANS, WE
影响因子：
20.3
作者：
Pui, CH;Sandlund, JT;Evans, WE
通讯作者：
Evans, WE