Unbiased Cell-Based Models to Identify GeneticVariants Associated with Chemotherapeutic Induced Toxicity

CN01-01 The International HapMap Project provides a key resource of genotypic data in human lymphoblastoid cell lines (LCLs) derived from populations of European, African, Chinese and Japanese ancestry to associate with various phenotypic data to find genes affecting disease and response to drugs. These cell lines have allowed for the exploration of quantitative variation in complex traits such as gene expression and dug response in human populations. To identify genetic variants that contribute to gene expression and chemotherapy-induced cytotoxicity, we developed unbiased, whole genome cell based models. By integrating genotype, gene expression and sensitivity of HapMap cell lines to chemotherapeutic drugs, we built predictive models to identify genetic signatures for susceptibility to chemotherapy-induced cytotoxicity. Cell lines derived from 30 trios of European descent (CEU) and 30 trios of African descent (YRI) were utilized. Cell growth inhibition at increasing concentrations of chemotherapeutic agents (etoposide, daunorubicin, AraC, cisplatin or carboplatin) was evaluated. Gene expression of 176 HapMap cell lines (87 CEU and 89 YRI) was determined using the Affymetrix GeneChip ® Human exon 1.0 ST Array. SNP genotype and the IC 50 (concentration required to inhibit 50% cell growth) of each agent were linked through whole genome association in cell lines from combined and independent CEU and YRI populations. A second association test was performed between SNP genotype and gene expression, and linear regression was then utilized to evaluate the correlation between gene expression and drug IC 50 . We identified genetic variants that significantly associate with sensitivity to the cytotoxic effects of these chemotherapeutic agents through differences in gene expression in the combined CEU and YRI populations, as well as each population individually. A multivariate model indicated that these limited numbers of genetic variants explained approximately 20-65% of the observed human variation in cellular sensitivity to chemotherapy. There are advantages and limitations in the use of LCLs in pharmacogenomic discovery that will be discussed as well as the wide range of cellular phenotypes that can be studied in these cell lines to ultimately gain insight as to how genetic variation contributes to phenotypic variation. These cell lines provide a novel means to answer important pharmacogenomic questions. This Pharmacogenetics of Anticancer Agents Research (PAAR) Group (http://pharmacogenetics.org) study was supported by NIH/NIGMS grant UO1GM61393.