Pharmacogenetics of outcome in children with acute lymphoblastic leukemia
Pharmacogenetics of outcome in children with acute lymphoblastic leukemia
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DOI：
10.1182/blood-2004-11-4544
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发表时间：
2005-06-15
期刊：
影响因子：
20.3
通讯作者：
Relling, MV
中科院分区：
文献类型：
--
作者：
Rocha, JCC;Cheng, C;Relling, MV
急性淋巴细胞白血病 (ALL) 细胞的获得性遗传特征用于个体化治疗，而生殖系遗传特征通常不用于个体化治疗。我们确定 ALL 结局是否与影响抗白血病药物药效学的 16 种基因多态性有关。在 246 名儿童中，116 名接受 St Jude 方案的低风险 (LR) 治疗，130 名接受高风险 (HR) 治疗。 HR 组中具有谷胱甘肽 S-转移酶 (GSTM1) 非无效基因型的患者具有较高的血液学复发风险 (P = .03)，而胸苷酸合成酶 (TYMS) 3/3 基因型则进一步增加了这种风险 (P = .03)。这些基因型在多变量分析中仍然具有预测性（分别 P < .001 和 .003）。 LR 组中没有可预测的基因型。在具有低活性基因型的所有胚细胞中，这 2 个基因的表达较低。对于中枢神经系统复发，在 HR 组中，维生素 D 受体起始位点 (P = .02) 和内含子 8 基因型 (P = .04) 易感，而 LR 患者则易感 TYMS 3/3 基因型 (P = .04)。 GSTM1 nonnull 和 TYMS 3/3 基因型似乎与耐药性相关。多态性相互作用影响抗白血病结果并代表可用于优化治疗的反应决定因素。 (c) 2005 年，美国血液学会。
Acquired genetic characteristics of acute lymphoblastic leukemia (ALL) cells are used to individualize therapy, whereas germ line genetic characteristics generally are not. We determined whether ALL outcome was related to 16 genetic polymorphisms affecting the pharmacodynamics of antileukemic agents. Of 246 children, 116 were treated on the lower-risk (LR) and 130 on the higher-risk (HR) arms of a St Jude protocol. Patients in the HR group with the glutathione S-transferase (GSTM1) nonnull genotype had greater risk of hematologic relapse (P = .03), which was further increased by the thymidylate synthetase (TYMS) 3/3 genotype (P = .03). These genotypes remained predictive in multivariate analyses (P < .001 and .003, respectively). No genotypes were predictive in the LR arm. Expression of these 2 genes in ALL blasts was lower in those with low-activity genotypes. For central nervous system relapse, among the HR group, the vitamin D receptor start site (P = .02) and intron 8 genotypes (P = .04) predisposed, whereas for LR patients the TYMS 3/3 genotype predisposed (P = .04). The GSTM1 nonnull and TYMS 3/3 genotypes are plausibly linked to drug resistance. Polymorphisms interact to influence antileukemic outcome and represent determinants of response that can be used to optimize therapy. (c) 2005 by The American Society of Hematology.