RRM1 and RRM2 pharmacogenetics: association with phenotypes in HapMap cell lines and acute myeloid leukemia patients.
RRM1 and RRM2 pharmacogenetics: association with phenotypes in HapMap cell lines and acute myeloid leukemia patients.
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DOI：
10.2217/pgs.13.131
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发表时间：
2013-09
期刊：
影响因子：
2.1
通讯作者：
Lamba JK
中科院分区：
文献类型：
--
作者：
Cao X;Mitra AK;Pounds S;Crews KR;Gandhi V;Plunkett W;Dolan ME;Hartford C;Raimondi S;Campana D;Downing J;Rubnitz JE;Ribeiro RC;Lamba JK
核糖核苷酸还原酶在细胞生成脱氧核糖核苷三磷酸的过程中催化一个关键步骤，并且与接受基于核苷类似物化疗的癌症患者的临床结果相关。
在当前研究中，我们对来自具有欧洲（具有北欧和西欧血统的犹他州居民[CEU]；n = 90）或非洲（尼日利亚伊巴丹的约鲁巴人[YRI]；n = 90）血统的国际人类基因组单体型图（HapMap）细胞系的基因组DNA中的RRM1和RRM2基因进行了测序。
我们鉴定出44个遗传变异，包括RRM1中的8个编码单核苷酸多态性（SNP）以及15个SNP，其中包括RRM2中的1个编码SNP。在CEU和YRI淋巴母细胞系以及急性髓系白血病（AML）患者（AML97，n = 89；AML02，n = 187）的白血病原始细胞中，RRM1和RRM2的mRNA表达水平彼此显著相关。此外，在表明复发风险高的患者特征中，RRM1表达更高。我们评估了来自CEU和YRI组的HapMap淋巴母细胞系中RRM1和RRM2基因内的SNP与表达和阿糖胞苷化疗敏感性的关联。在AML患者中进一步评估了具有潜在重要性的SNP。RRM1的SNP rs1042919（与多个其他SNP处于连锁不平衡状态）和启动子SNP rs1561876与细胞内1 - β - D - 阿拉伯呋喃糖基 - 胞苷三磷酸（1 - β - D - arabinofuranosyl - CTP）水平、缓解诱导治疗后的反应、复发风险以及接受阿糖胞苷和克拉屈滨治疗的AML患者的总生存期相关。
这些结果表明，核糖核苷酸还原酶内的SNP可能是对核苷类似物反应的有用预测标志物，并且应该在更大的队列中进一步验证。
Ribonucleotide reductase catalyzes an essential step in the cellular production of deoxyribonucleotide triphosphates and has been associated with clinical outcome in cancer patients receiving nucleoside analog-based chemotherapy. In the current study, we sequenced the genes RRM1 and RRM2 in genomic DNA from HapMap cell lines with European (Utah residents with northern and western European ancestry [CEU]; n = 90) or African (Yoruba people in Ibadan, Nigeria [YRI]; n = 90) ancestry. We identified 44 genetic variants including eight coding SNPs in RRM1 and 15 SNPs including one coding SNP in RRM2. RRM1 and RRM2 mRNA expression levels were significantly correlated with each other in both CEU and YRI lymphoblast cell lines, and in leukemic blasts from acute myeloid leukemia (AML) patients (AML97, n = 89; AML02, n = 187). Additionally, RRM1 expression was higher among patient features indicative of a high relapse hazard. We evaluated SNPs within the RRM1 and RRM2 genes in the HapMap lymphoblast cell lines from CEU and YRI panels for association with expression and cytarabine chemosensitivity. SNPs of potential significance were further evaluated in AML patients. RRM1 SNPs rs1042919 (which occurs in linkage disequilbrium with multiple other SNPs) and promoter SNP rs1561876 were associated with intracellular 1-β-D-arabinofuranosyl-CTP levels, response after remission induction therapy, risk of relapse and overall survival in AML patients receiving cytarabine and cladribine. These results suggest that SNPs within ribonucleotide reductase might be helpful predictive markers of response to nucleoside analogs and should be further validated in larger cohorts.
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作者：
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