Genome-wide association study for biomarker identification of Rapamycin and Everolimus using a lymphoblastoid cell line system.
Genome-wide association study for biomarker identification of Rapamycin and Everolimus using a lymphoblastoid cell line system.
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DOI：
10.3389/fgene.2013.00166
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发表时间：
2013
影响因子：
3.7
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Jiang J;Fridley BL;Feng Q;Abo RP;Brisbin A;Batzler A;Jenkins G;Long PA;Wang L
哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂是一组有前途的潜在抗癌药物，已显示出个体间的反应差异。本研究旨在确定可能影响雷帕霉素和依维莫司反应的新生物标志物和机制。全基因组关联（GWA）分析涉及单核苷酸多态性（SNP），mRNA和microRNA微阵列数据，评估了与272人淋巴母细胞样细胞系（LCL）中两种mTOR抑制剂的细胞毒性剂量反应曲线下面积（AUC）的关联。还进行了SNP、表达数据、microRNA数据和AUC值之间的综合分析，以帮助选择候选基因用于进一步的功能表征。在多个细胞系中使用siRNA筛选进行候选基因的功能验证，随后进行两种mTOR抑制剂的MTS测定。我们发现，两种药物之间重叠的16个表达探针集（基因）与两种mTOR抑制剂的AUC值相关。分别有127个和100个SNP的P <10 − 4，而8个和10个SNP的P <10 − 5与雷帕霉素和依维莫司AUC相关。功能研究表明，13个基因显着改变细胞敏感性的一种或两种药物在至少一个细胞系。此外，一种microRNA，miR-10a，与两种药物的AUC值显著相关，并显示抑制与AUC相关的基因的表达，并使细胞对两种药物脱敏。总之，这项研究确定了可能有助于对mTOR抑制剂反应的基因和microRNA。
The mammalian target of rapamycin (mTOR) inhibitors, a set of promising potential anti-cancer agents, has shown response variability among individuals. This study aimed to identify novel biomarkers and mechanisms that might influence the response to Rapamycin and Everolimus. Genome-wide association (GWA) analyses involving single nucleotide polymorphisms (SNPs), mRNA, and microRNAs microarray data were assessed for association with area under the cytotoxicity dose response curve (AUC) of two mTOR inhibitors in 272 human lymphoblastoid cell lines (LCLs). Integrated analysis among SNPs, expression data, microRNA data and AUC values were also performed to help select candidate genes for further functional characterization. Functional validation of candidate genes using siRNA screening in multiple cell lines followed by MTS assays for the two mTOR inhibitors were performed. We found that 16 expression probe sets (genes) that overlapped between the two drugs were associated with AUC values of two mTOR inhibitors. One hundred and twenty seven and one hundred SNPs had P < 10−4, while 8 and 10 SNPs had P < 10−5 with Rapamycin and Everolimus AUC, respectively. Functional studies indicated that 13 genes significantly altered cell sensitivity to either one or both drugs in at least one cell line. Additionally, one microRNA, miR-10a, was significantly associated with AUC values for both drugs and was shown to repress expression of genes that were associated with AUC and desensitize cells to both drugs. In summary, this study identified genes and a microRNA that might contribute to response to mTOR inhibitors.