Discovery of genetic profiles impacting response to chemotherapy: application to gemcitabine

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 NCI60 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 gemcitabine. 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 NCI60 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.