Identification of Genetic Variants Contributing to Cisplatin-Induced Cytotoxicity using a Genome-wide Approach

Cisplatin, a platinating agent commonly used in treating several cancers is associated with nephrotoxicity, neurotoxicity and ototoxicity that have hindered its utility. To gain a better understanding of the genetic variants associated with cisplatin induced toxicity, we present a step-wise 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 utilized 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 on 176 HapMap cell lines (87 CEU and 89 YRI) was determined using the Affymetrix GeneChip® Human Exon 1.0 ST Array. We identified 6, 2 and 9 representative SNPs that contribute to cisplatin-induced cytotoxicity through their effects on 8, 2 and 16 gene expressions in the combined, 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 expression quantitative trait loci contributing to a wide range of cellular phenotypes. Keywords: exon array Gene expression on 176 HapMap cell lines.