Gemcitabine and arabinosylcytosin pharmacogenomics: genome-wide association and drug response biomarkers.
Gemcitabine and arabinosylcytosin pharmacogenomics: genome-wide association and drug response biomarkers.
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DOI：
10.1371/journal.pone.0007765
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发表时间：
2009-11-09
期刊：
影响因子：
3.7
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Li L;Fridley BL;Kalari K;Jenkins G;Batzler A;Weinshilboum RM;Wang L
癌症患者对化疗药物的反应存在较大的个体差异。吉西他滨（dFdC）和AraC，两个胞苷类似物，已显示出显着的活性，对各种肿瘤。我们以前使用的表达数据从淋巴母细胞系为基础的模型系统，以确定基因，可能是重要的两种药物的细胞毒性。在本研究中，我们使用相同的模型系统进行全基因组关联（GWA）研究，以检验共同的遗传变异可能影响基因表达和对两种药物的反应的假设。具体地，分别使用Illumina 550 K ® HumanHap 550 SNP芯片和Affytek U133 Plus 2.0 GeneChip获得174个种族定义的“Human Variation Panel”淋巴母细胞样细胞系的全基因组单核苷酸多态性（SNP）和mRNA表达数据。进行吉西他滨和AraC细胞毒性测定以获得细胞系的IC 50值。然后，我们对这两种药物的SNP、基因表达和IC 50进行了GWA研究。该方法鉴定了分别与吉西他滨或AraC IC 50值以及与29个基因或30个基因的表达调控相关的SNP。IQGAP 2中的一个SNP（rs3797418）与多个基因的表达以及吉西他滨和AraC IC 50的变化显著相关。TGM 3中的第二个SNP（rs6082527）也与多基因表达和吉西他滨IC 50显著相关。为了证实关联结果，我们对肿瘤细胞中与rs3797418和rs6082527表达相关的选定基因进行了siRNA敲低，敲低改变了吉西他滨或AraC的敏感性，证实了我们的关联研究结果。这些结果表明，GWA方法的应用，使用基于细胞的模型系统，当与互补功能验证相结合时，可以提供深入了解的机制，负责变化的胞苷类似物的反应。
Cancer patients show large individual variation in their response to chemotherapeutic agents. Gemcitabine (dFdC) and AraC, two cytidine analogues, have shown significant activity against a variety of tumors. We previously used expression data from a lymphoblastoid cell line-based model system to identify genes that might be important for the two drug cytotoxicity. In the present study, we used that same model system to perform a genome-wide association (GWA) study to test the hypothesis that common genetic variation might influence both gene expression and response to the two drugs. Specifically, genome-wide single nucleotide polymorphisms (SNPs) and mRNA expression data were obtained using the Illumina 550K® HumanHap550 SNP Chip and Affymetrix U133 Plus 2.0 GeneChip, respectively, for 174 ethnically-defined “Human Variation Panel” lymphoblastoid cell lines. Gemcitabine and AraC cytotoxicity assays were performed to obtain IC50 values for the cell lines. We then performed GWA studies with SNPs, gene expression and IC50 of these two drugs. This approach identified SNPs that were associated with gemcitabine or AraC IC50 values and with the expression regulation for 29 genes or 30 genes, respectively. One SNP in IQGAP2 (rs3797418) was significantly associated with variation in both the expression of multiple genes and gemcitabine and AraC IC50. A second SNP in TGM3 (rs6082527) was also significantly associated with multiple gene expression and gemcitabine IC50. To confirm the association results, we performed siRNA knock down of selected genes with expression that was associated with rs3797418 and rs6082527 in tumor cell and the knock down altered gemcitabine or AraC sensitivity, confirming our association study results. These results suggest that the application of GWA approaches using cell-based model systems, when combined with complementary functional validation, can provide insights into mechanisms responsible for variation in cytidine analogue response.
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