Originally published as JCO Early Release 10.1200/JCO.2005.03.0825 on September 6 2005

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Pharmacogenomic Discovery Approaches: Will the Real Genes Please Stand Up?

Richard A. Walgren, Melissa A. Meucci, Howard L. McLeod

From the Departments of Medicine, Molecular Biology and Pharmacology, and Genetics, Washington University School of Medicine; and The Siteman Cancer Center, St Louis, MO

Address reprint requests to Howard L. McLeod, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8069, St Louis, MO 63110; e-mail: hmcleod{at}im.wustl.edu.

Genetic inheritance plays a significant role in the interindividual variability of drug response. The field of pharmacogenomics seeks to identify genetic factors that influence drug response, including both those that are inherited and those that arise within tumors, and use this information to improve drug therapy. Candidate gene approaches have led to clinical tests for toxicity avoidance (eg, TPMT, UGT1A1) and efficacy prediction (eg, epidermal growth factor receptor–activating mutations). However, the "right" genes are not known for most anticancer drugs. Strategies for uncovering pharmacogenomic associations vary widely from monogenic candidate gene approaches to polygenic genome-wide approaches. This review will place in context clinically relevant pharmacogenomic discovery approaches, including the relative strengths and weaknesses and the challenges inherent with achieving the goal of individualized therapy.

Supported in part by National Institutes of Health Grants No. UO1 GM63340, R21 CA102461, R21 CA113491, and P01 CA101937. R.W. receives support from Grant No. T32-HL07088-30.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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