A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients
A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients
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DOI：
10.1093/annonc/mdn548
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发表时间：
2009-01-01
影响因子：
50.5
通讯作者：
Krex, D.
中科院分区：
文献类型：
--
作者：
Schaich, M.;Kestel, L.;Krex, D.
背景：一些多形性胶质母细胞瘤患者即使存在DNA修复酶O-6-甲基鸟嘌呤甲基转移酶(MGMT)的异常启动子甲基化，对替莫唑胺也没有反应。这表明，额外的因素阻碍了替莫唑胺的细胞毒性。我们的目标是首先确认替莫唑胺是多药耐药转运体MDR1/ABCB1的靶点，然后研究MDR1基因的遗传变异是否与使用替莫唑胺治疗的胶质母细胞瘤患者的生存有关。材料和方法：用甲基四氮唑比色法测定表达MDR和不表达MDR的胶质母细胞瘤细胞株中替莫唑胺介导的细胞毒性。对112例接受手术加放疗或联合替莫唑胺化疗的胶质母细胞瘤患者的mdr1基因C1236T、G2677T和C3435T三个单核苷酸多态性(SNPs)、mdr1基因表达水平和MGMT启动子甲基化状态进行分析。结果：体外分析表明替莫唑胺介导的细胞毒作用依赖于mdr1的表达。MDR1基因多变量分析显示，外显子12 C1236T SNP的C/C变异可预测替莫唑胺治疗患者的生存。这种影响与MGMT甲基化状态无关。C/C基因携带者的2年总生存率为37%，而C/T和T/T基因携带者分别为8%和10%(P=0.02)。结论：mdr1基因外显子12 C1236T SNP是预测替莫唑胺治疗胶质母细胞瘤疗效的一个新的独立因素。
Background: Some patients with glioblastoma multiform do not respond to temozolomide even though they have aberrant promoter methylation of the DNA repair enzyme O-6-methylguanine methyltransferase (MGMT). This suggests that additional factors hamper temozolomide cytotoxicity. We aimed to confirm first that temozolomide is a target for the multidrug resistance transporter MDR1/ABCB1 and second to investigate whether genetic variants of the MDR1 gene are associated with the survival of glioblastoma patients treated with temozolomide.Materials and methods: Temozolomide-mediated cytotoxicity was determined by the colorimetric methyl-thiazol-tetrazolium assay in MDR-expressing and MDR-nonexpressing cell lines. Genotypes of three single nucleotide polymorphisms (SNPs) of the MDR1 gene (C1236T, G2677T, and C3435T), MDR1 mRNA expression levels, and the MGMT promoter methylation status were analyzed in 112 glioblastoma patients who had been treated either by surgery plus radiotherapy alone or by additional temozolomide chemotherapy.Results: In vitro analysis revealed that temozolomide-mediated cytotoxicity is dependent on MDR1 expression. Multivariate analysis of MDR1 genotypes showed that the C/C variant of the exon12 C1236T SNP is predictive for survival of patients treated with temozolomide. This effect was independent of the MGMT methylation status. Patients with the C/C genotype had a 2-year overall survival of 37% compared with 8% and 10% for patients with C/T and T/T genotypes, respectively (P = 0.02). No influence was seen in the group of patients with radiotherapy only.Conclusion: The genotype of the MDR1 exon12 C1236T SNP is a novel independent predictive factor for outcome of temozolomide treatment in glioblastoma patients.