Silent polymorphisms speak: how they affect pharmacogenomics and the treatment of cancer.
Polymorphisms in the human genome contribute to wide variations in how individuals respond to medications, either by changing the pharmacokinetics of drugs or by altering the cellular response to therapeutic agents. The goal of the emerging discipline of pharmacogenomics is to personalize therapy based on an individual's genotype. Due to the relatively large frequency of single-nucleotide polymorphisms (SNP) in the human genome, synonymous SNPs are often disregarded in many pharmacogenomic studies based on the assumption that these are silent. We have shown recently that synonymous SNPs in ABCB1 (P-glycoprotein), which is implicated both in determining drug pharmacokinetics and multidrug resistance in human cancer cells, can affect protein conformation and function. We discuss the importance of polymorphisms in drug metabolizing enzymes and transporters in anticancer therapy and suggest that synonymous polymorphisms may play a more significant role than is currently assumed.
Sauna
Zuben E
ZE
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH and Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Kimchi-Sarfaty
Chava
C
Ambudkar
Suresh V
SV
Gottesman
Michael M
MM
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents