Pharmacoepigenetics explores the epigenetic contribution to anti-cancer agent-induced cytotoxicities

Elucidating genetic and epigenetic contributions to drug response variation is critical for the realization of personalized medicine, which may particularly benefit cancer patients, for whom anti-cancer agent-induced cytotoxicities are often major adverse reactions. Previous pharmacogenomic discoveries have utilized the HapMap lymphoblastoid cell line (LCL) model, on which the research community has accumulated extensive genotypic data and gene expression profiles. Given the complex nature of gene expression regulation, expanding the cell-based model to include epigenetic systems such as cytosine modifications has begun to allow novel pharmacoepigenetic studies that may enhance our understanding of drug response variation. Using a collection of the HapMap LCL samples, our team has profiled the genome-wide cytosine modification levels and explored the contribution of CpG modifications to anti-cancer agent-induced cytotoxicities. Specifically, in our recent pharmacogenomic study on clofarabine, we demonstrated that by integrating cytosine modifications, genetic variants, and gene expression phenotypes, we were able to significantly improve our ability to explain the phenotypic variance among individuals. Finally, advances in experimental techniques that can distinguish 5’methylcytosine (5mC) and 5’-hydroxymethylcytosine (5hmC), the latter of which is a recently rediscovered nucleotide base in the human genome with potential unique biological functions, as well as stem cell technologies that can differentiate target tissues from induced pluripotent stem cells (iPSCs), will move forward the current pharmacoepigenetic and pharmacogenomic research to the next stage with higher molecular resolution and better clinical relevance.