Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach
Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach
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DOI：
10.1086/519850
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发表时间：
2007-09-01
影响因子：
9.8
通讯作者：
Dolan, M. Eileen
中科院分区：
文献类型：
--
作者：
Huang, R. Stephanie;Duan, Shiwei;Dolan, M. Eileen
顺铂是一种常用于治疗几种癌症的铂化剂，与肾毒性、神经毒性和耳毒性相关，这阻碍了其效用。为了更好地了解与顺铂诱导的毒性相关的遗传变异，我们提出了一种逐步整合基因型，基因表达和HapMap细胞系对顺铂的敏感性的方法。来自30个欧洲血统（CEU）和30个非洲血统（YRI）的三人组的细胞系用于开发临床前模型，以鉴定两个不同人群中导致顺铂诱导细胞毒性的遗传变异和基因表达。细胞毒性测定为顺铂浓度增加48 h时的细胞生长抑制。使用Affyssin GeneChip Human Exon 1.0 ST Array测定176个HapMap细胞系（87个CEU和89个YRI）中的基因表达。我们确定了六个，两个和九个代表性的SNP，有助于顺铂诱导的细胞毒性，通过其对8，2和16个基因表达的组合，中心研究杜多态性人类（CEPH），约鲁班人口，分别影响。这些遗传变异分别占合并、CEPH和约鲁班人群中细胞对顺铂敏感性总体变异的27%、29%和45%。我们的全基因组方法可用于阐明数量性状基因座的表达，有助于广泛的细胞表型。
Cisplatin, a platinating agent commonly used to treat several cancers, is associated with nephrotoxicity, neurotoxicity, and ototoxicity, which has hindered its utility. To gain a better understanding of the genetic variants associated with cisplatin-induced toxicity, we present a stepwise approach integrating genotypes, gene expression, and sensitivity of HapMap cell lines to cisplatin. Cell lines derived from 30 trios of European descent (CEU) and 30 trios of African descent (YRI) were used to develop a preclinical model to identify genetic variants and gene expression that contribute to cisplatin-induced cytotoxicity in two different populations. Cytotoxicity was determined as cell-growth inhibition at increasing concentrations of cisplatin for 48 h. Gene expression in 176 HapMap cell lines (87 CEU and 89 YRI) was determined using the Affymetrix GeneChip Human Exon 1.0 ST Array. We identified six, two, and nine representative SNPs that contribute to cisplatin-induced cytotoxicity through their effects on 8, 2, and 16 gene expressions in the combined, Centre d'Etude du Polymorphisme Humain (CEPH), and Yoruban populations, respectively. These genetic variants contribute to 27%, 29%, and 45% of the overall variation in cell sensitivity to cisplatin in the combined, CEPH, and Yoruban populations, respectively. Our whole-genome approach can be used to elucidate the expression of quantitative trait loci contributing to a wide range of cellular phenotypes.