Primer on medical genomics. Part XII: Pharmacogenomics--general principles with cancer as a model

The Human Genome Project has resulted in a new era in the field of pharmacogenetics in which researchers are rapidly discovering new genetic variation, which may help to explain interindividual variability in drug efficacy and toxicity. Pharmacogenetics is the study of the role of genetic inheritance in individual variation in drug response and toxicity. With the convergence of advances in pharmacogenetics and human genomics, the field of pharmacogenomics has emerged during the past decade. Pharmacogenomics is used to refer to the study of the relationship between specific DNA-sequence variation and drug effect. In few other disciplines of medicine are the clinical examples of pharmacogenetics more striking than in oncology. In this field, treatment of patients with cancer is accomplished primarily through the use of chemotherapeutic drugs that have narrow therapeutic indexes, ie, the difference between the toxic and therapeutic dose is relatively small. In this review, we discuss several selected, clinically relevant examples of ways in which sequence variation in genes that encode drug enzymes, transporters, and drug targets can alter the efficacy and/or adverse-effect profile of "standard" doses of chemotherapeutic drugs. Additionally, we discuss some of the ways in which physicians are currently applying this knowledge in the treatment of patients with cancer.