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A 72-year-old male with metastatic colorectal cancer was prescribed an anti-cancer drug, irinotecan 180 mg/m2, as an intravenous infusion, which was repeated every two weeks, along with several other chemotherapeutic agents. Liver function and renal function were normal. Blood samples were drawn. After the first treatment cycle, the patient experienced very severe neutropenia and diarrhea. Plasma levels of SN-38, the active metabolite of irinotecan, were fourfold higher than those found in most patients. The irinotecan dose was reduced by 50% (to 90 mg/m2), and plasma levels of SN-38 were lower but were still more than twice normal. However, after the second cycle, there was no neutropenia and only grade 1 diarrhea. Computerized tomography and magnetic resonance imaging scans showed a partial response to the chemotherapy. Could a UGT1A1*28 polymorphism have led to the adverse effects?

Pharmacogenomics, the study of genetic factors that underlie variation in drug response, is a modern term for pharmacogenetics. Pharmacogenomics implies a recognition that more than one genetic variant may contribute to variation in drug response. Historically, the field began with observations of severe adverse drug reactions in certain individuals, who were found to harbor genetic variants in drug-metabolizing enzymes. As a scientific field, pharmacogenomics has advanced rapidly since the sequencing of the human genome. In the last decade, powerful genomewide association (GWA) studies, in which hundreds of thousands of genetic variants across the genome are tested for association with drug response, led to the discovery of many other important polymorphisms that underlie variation in both therapeutic and adverse drug response. In addition to polymorphisms in genes that encode drug-metabolizing enzymes, it is now known that polymorphisms in genes that encode transporters, human leukocyte antigen (HLA) loci, cytokines, and various other proteins are also predictive of variation in therapeutic and adverse drug responses. In addition to the new discoveries that have been made, the past decade has ushered in “genome medicine,” also known as “personalized medicine,” in which genetic information is used to guide drug and dosing selection for individual patients in medical practice. The Clinical Pharmacogenetics Implementation Consortium (CPIC) published a series of guidelines for using genetic information in selecting medications and in dosing. These highly informative guidelines are being used by practitioners in prescribing drugs to more effectively treat patients. In this chapter, we begin with a case study and then describe genetic variants that are determinants of drug response. Where appropriate, CPIC recommendations are included to provide information on how to use genetic variant data appropriately in therapeutic medicine.

The description in this chapter of DNA sequence variations in germline DNA involves a number of terms that describe the nature of the variations and their locations within the genome. A glossary of commonly used terms is presented in the Glossary Table. Some of the more common and important variations are described in the text that follows.


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