Primer on Medical Genomics Part XII Mayo Clin Proc, March 2004, Vol 79 376 Mayo Clin Proc. 2004;79:376-384 376 © 2004 Mayo Foundation for Medical Education and Research Medical Genomics Primer on Medical Genomics Part XII: Pharmacogenomics—General Principles With Cancer as a Model MATTHEW P. GOETZ, MD; MATTHEW M. AMES, PHD; AND RICHARD M. WEINSHILBOUM, MD From the Department of Oncology (M.P.G., M.M.A.) and Department of Molecular Pharmacology and Experimental Therapeutics (M.M.A., R.M.W.), Mayo Clinic College of Medicine, Rochester, Minn. Dr Weinshilboum is a member of the Mayo Clinic Genomics Education Steering Committee. This study was supported in part by grant CA90628 from the National Cancer Institute (M.P.G.) and grants GM28157, GM35720, and GM61388 from the National Institutes of Health (R.M.W.). Individual reprints of this article are not available. The entire Primer on Medical Genomics will be available for purchase from the Pro- ceedings Editorial Office at a later date. CPT-11 = irinotecan; DPD = dihydropyrimidine dehydroge- nase; 5-FdUMP = 5-fluoro-2-deoxyuridine monophosphate; 5-FU = 5-fluorouracil; 4-OH-tam = 4-hydroxytamoxifen; SULT = sulfotransferase; TMPT = thiopurine S-methyltrans- ferase; TS = thymidylate synthase; UGT1A1 = uridine diphos- phate glucuronosyltransferase 1A1; UV = ultraviolet A lthough many clinical variables can contribute to variation in drug response (age, sex, diet, organ func- tion), genetic variation in the genes that influence drug disposition and drug targets is recognized increasingly as one of the principal variables that can influence drug effect. The concepts that underlie pharmacogenetics originated many years ago from the clinical observation that adminis- tration of the same dose of a given drug could result in marked variability in efficacy and toxicity, followed by the realization that inheritance could be a major factor respon- sible for that variance. Only later were the proteins (ini- tially drug-metabolizing enzymes) responsible for this variation identified, followed by the genes that encoded those proteins and the DNA sequence variation within the genes that was associated with the inherited trait. Most of those original pharmacogenetic traits were monogenic, ie, they involved only a single gene, and most were due to 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 ge- netic inheritance in individual variation in drug response and toxicity. With the convergence of advances in pharma- cogenetics and human genomics, the field of pharmaco- genomics has emerged during the past decade. Pharmaco- genomics 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 ex- amples of pharmacogenetics more striking than in oncol- ogy. In this field, treatment of patients with cancer is accomplished primarily through the use of chemothera- peutic drugs that have narrow therapeutic indexes, ie, the difference between the toxic and therapeutic dose is rela- tively 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. Mayo Clin Proc. 2004;79:376-384 genetic polymorphisms, ie, the allele or alleles responsible for the variation were relatively common. One of the earli- est observations was that individuals with an inherited deficiency in the enzyme butyrylcholinesterase had pro- longed paralysis and consequent apnea after the adminis- tration of succinylcholine. 1 Later, researchers discovered that the DNA sequence variation within the gene that en- codes for butyrylcholinesterase could significantly alter the clearance of succinylcholine, leading to the clinical obser- vation of prolonged apnea. 2 Although drug effect is a complex phenotype that en- compasses many factors, those early and often dramatic examples facilitated acceptance of the fact that inheritance could be an important factor influencing drug effect. To- day, that original bedside to bench flow of pharmacoge- netic information (the so-called phenotype to genotype approach) is being supplemented by a systematic search for functionally significant DNA sequence variation within genes of importance for drug effect. Much of this genetic variation is in the form of single nucleotide polymorphisms (defined as variants with frequencies of ≥1%), which can alter the amino acid sequence of the encoded protein, alter RNA splicing, or alter transcription. After the identifica- tion of specific DNA sequence variants, investigators are able to establish quickly in vitro whether that variation results in a functional change in phenotype (eg, altered expression of RNA and/or change in protein levels). This For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.