Discovery of genetic profiles impacting response to chemotherapy: Application to gemcitabine
Discovery of genetic profiles impacting response to chemotherapy: Application to gemcitabine
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DOI：
10.1002/humu.20732
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发表时间：
2008-04-01
期刊：
影响因子：
3.9
通讯作者：
Ozcelik, Hilmi
中科院分区：
文献类型：
--
作者：
Jarjanazi, Hamdi;Kiefer, Jeffrey;Ozcelik, Hilmi
化疗是受癌症影响的个体的主要治疗方式。目前，许多基于基因组的技术正在被采用来鉴定与药物反应相关的基因;然而，大规模的遗传关联应用仍然有限。在这里，我们描述了一种新的策略的基础上的遗传和药物反应数据的NC 160细胞系，以发现潜在的候选基因变异与可变的化疗反应。作为一个例子，我们已经应用这种策略，发现单一的遗传标记和单倍型候选基因先前涉及的吉拉西他滨的药理学。单标记关联分析表明，CDC 5L、EPC 2、POLS和PARP 1基因座内的4个SNP之间存在关联。我们还使用基于单体型的分析研究了SNP的组合效应。因此，我们已经表明在六个基因的单倍型适度的协会，而最显着的协会包括POLS基因的单倍型。本研究中提出的假设生成工具可应用于NC 160细胞系筛选中的药物，并为鉴定与药物反应相关的基因提供了有效手段。该方法的研究结果可为临床化疗药物的有效性研究提供依据。
Chemotherapy is a major treatment modality for individuals affected by cancer. Currently, a number of genome based technologies are being adopted to identify genes associated with drug response; however, large-scale genetic association applications are still limited. Here we describe a novel strategy based on the genetic and drug response data of the NC160 cell lines to discover potential candidate genetic variants associated with variable response to chemotherapy. As an example we have applied this strategy to discover single genetic markers and haplotypes from candidate genes previously implicated in the pharmacobiology of geracitabine. Single marker association analyses have implicated the association of four SNPs within the gene loci of CDC5L, EPC2, POLS, and PARP1. We have also investigated the combined effect of SNPs using haplotype-based analysis. Accordingly, we have shown modest association of haplotypes in six genes, whereas the most significant associations included a haplotype of the POLS gene. The hypothesis-generating tool presented in this study can be applied to drugs profiled in the NC160 cell line screen and provides an effective means for the identification of genes associated with drug response. The results obtained using this novel methodology can be used to better design the clinical trials for effective study of the chemotherapeutic agents and thus provide a basis for individualized chemotherapy.