Abstract:
Acute lymphoblastic leukemia (ALL) is the most frequent pediatric cancer. 6-Mercaptopurine (6-MP) is a key component of ALL treatment. Its use, however, is also associated with adverse drug reactions, particularly myelosuppression. Thiopurine S-methyltransferase (TPMT) and, more recently, Nudix hydrolase 15 (NUDT15) deficiency, due to no-function variants in their respective genes, are well known for their role in the development of this toxicity. Two novel genetic variants, rs12199316 in TPMT and rs73189762 in the NUDT15 gene, were recently identified by targeted sequencing. The latter is particularly interesting because of its potential association with 6-MP intolerance. Here, we assessed the relationship of this variant with the risk of myelosuppression and 6-MP dose intensity in 275 patients treated with Dana Farber Cancer Institute ALL protocols at the Sainte Justine University Health Center. Carriers of the NUDT15 rs73189762 variant allele were at a higher risk of myelosuppression, as shown by absolute phagocyte count reduction during consolidation II and maintenance phases of therapy. Reduction in 6-MP dose intensity was observed in patients with both rs73189762 and known no-function variants in the NUDT15 and TPMT genes. This finding supports the initial observation and suggests that 6-MP dose reduction might be beneficial for individuals with this genotype combination.
摘要:
急性淋巴细胞白血病(ALL)是最常见的儿科癌症。6-巯基嘌呤(6-MP)是ALL治疗的关键组成部分。它的使用,然而,也与药物不良反应有关,特别是骨髓抑制。硫嘌呤S-甲基转移酶(TPMT)和,最近,Nudix水解酶15(NUDT15)缺乏,由于各自基因的无功能变异,众所周知,它们在这种毒性发展中的作用。两个新的遗传变异,TPMT中的rs12199316和NUDT15基因中的rs73189762,最近通过靶向测序鉴定。后者由于其与6-MP不耐受的潜在关联而特别有趣。这里,我们在SainteJustine大学健康中心接受DanaFarber癌症研究所ALL方案治疗的275例患者中评估了该变异与骨髓抑制风险和6-MP剂量强度的关系.NUDT15rs73189762变异等位基因的携带者有较高的骨髓抑制风险,如在巩固II期和维持期治疗期间的绝对吞噬细胞计数减少所示。在具有rs73189762和NUDT15和TPMT基因中已知的无功能变体的患者中观察到6-MP剂量强度的降低。这一发现支持了最初的观察结果,并表明6-MP剂量减少可能对具有这种基因型组合的个体有益。