Cell-based Models for Discovery of Pharmacogenomic Markers of Anticancer Agent Toxicity

Abstract

The field of pharmacogenomics is challenging because of the multigenic nature of drug response and toxicity. The candidate gene approach has been traditionally utilized to determine the contribution of genetic variation to a particular phenotype; however, the sequencing of the human genome and the genetic resource provided by the International HapMap Project has allowed researchers to perform genome-wide studies without a priori knowledge. Recent work has demonstrated the usefulness of cell-based models for pharmacogenomic discovery using the HapMap samples, which are a panel of well-genotyped, human lymphoblastoid cell lines (LCLs) derived from 90 Utah residents with ancestry from northern and western Europe (CEU), 90 Yoruba in Ibadan, Nigeria (YRI), 45 Japanese in Tokyo, Japan (JPT) and 45 Han Chinese in Beijing, China (CHB). Using these cell-based models, investigators are able to study not only individual variation in drug response, but also population differences in drug response. Finally, besides single nucleotide polymorphisms (SNPs) and gene expression, these cell-based models can also be used to investigate other genetic (e.g. copy number variants, CNVs), epigenetic or environmental factors responsible for drug response.

Figure 1

LCL samples from the International HapMap Project are derived from individuals of European, African and Asian ancestry. CEU: Caucasians from Utah, USA; YRI: Yoruba people from Ibadan, Nigeria; CHB: Han Chinese from Beijing, China; JPT: Japanese from Tokyo, Japan.

Figure 2

Cell-based, genome-wide model to identify genetic variants important in drug cytotoxicity. Model includes whole genome association between SNP genotype and gene expression, association between genotype and gene expression and linear regression between gene expression and drug response.