Ben Tanfous Mohsen, Sharif-Askari Bahram, Ceppi Francesco, Laaribi Haithem, Gagné Vincent, Rousseau Julie, Labuda Malgorzata, Silverman Lewis B, Sallan Stephen E, Neuberg Donna, Kutok Jeffery L, Sinnett Daniel, Laverdière Caroline, Krajinovic Maja
Research Center, CHU Sainte-Justine; Departments of.
Pediatric Oncology; Division of Hematology/Oncology, Children's Hospital; and.
Clin Cancer Res. 2015 Jan 15;21(2):329-34. doi: 10.1158/1078-0432.CCR-14-0508. Epub 2014 Jun 6.
Asparaginase (ASNase) is a standard and critical component in the therapy of childhood acute lymphoblastic leukemia (ALL), but it is also associated with several toxicities.
We recently reported the results of an association study between ASNase pathway genes and event-free survival (EFS) in childhood patients with ALL. The same polymorphisms were interrogated here in relation to allergies, pancreatitis, and thrombotic events following treatment with E. coli ASNase.
Among patients of the discovery group, allergies, and pancreatitis were more frequent in individuals who are homozygous for the triple-repeat allele (3R) of the asparagine synthetase (ASNS) gene, resulting in remarkably higher risk of these toxicities associated with 3R3R genotype [OR for allergies, 14.6; 95% confidence interval (CI), 3.6-58.7; P < 0.0005 and OR for pancreatitis, 8.6; 95% CI, 2.0-37.3; P = 0.01]. In contrast, the ASNS haplotype *1 harboring double-repeat (2R) allele had protective effect against these adverse reactions (P ≤ 0.01). The same haplotype was previously reported to confer reduction in EFS. The risk effect of 3R3R genotype was not replicated in the validation cohort, whereas the protective effect of haplotype *1 against allergies was maintained (P ≤ 0.002). Analysis with additional polymorphisms in ASNS locus in lymphoblastoid cell lines showed that haplotype *1 is diversified in several subtypes of which one was associated with reduced in vitro sensitivity to ASNase (rs10486009, P = 0.01) possibly explaining an association seen in clinical setting.
This finding might have implication for treatment individualization in ALL and other cancers using asparagine depletion strategies. Clin Cancer Res; 21(2); 329-34. ©2014 AACR. See related commentary by Avramis, p. 230.
天冬酰胺酶（ASNase）是儿童急性淋巴细胞白血病（ALL）治疗中的标准且关键的组成部分，但它也与多种毒性反应相关。
我们最近报告了一项关于ALL儿童患者中天冬酰胺酶途径基因与无事件生存期（EFS）之间关联研究的结果。在此，针对大肠杆菌ASNase治疗后的过敏、胰腺炎和血栓形成事件，对相同的多态性进行了研究。
在发现组患者中，天冬酰胺合成酶（ASNS）基因三重复等位基因（3R）纯合个体的过敏和胰腺炎更为常见，导致与3R3R基因型相关的这些毒性反应风险显著更高[过敏的比值比（OR）为14.6；95%置信区间（CI）为3.6 - 58.7；P < 0.0005，胰腺炎的OR为8.6；95%CI为2.0 - 37.3；P = 0.01]。相比之下，携带双重复（2R）等位基因的ASNS单倍型1对这些不良反应具有保护作用（P≤0.01）。先前报道相同单倍型会使EFS降低。3R3R基因型的风险效应在验证队列中未得到重复，而单倍型1对过敏的保护作用得以维持（P≤0.002）。在淋巴母细胞系中对ASNS基因座的其他多态性进行分析表明，单倍型*1在几个亚型中存在差异，其中一个亚型与体外对ASNase的敏感性降低相关（rs10486009，P = 0.01），这可能解释了在临床环境中观察到的一种关联。
这一发现可能对使用天冬酰胺消耗策略的ALL及其他癌症的个体化治疗具有启示意义。《临床癌症研究》；21(2)；329 - 34。©2014美国癌症研究协会。见Avramis的相关评论，第230页。
