Pharmacogenomic Testing in the Clinical Laboratory: Historical Progress and Future Opportunities
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Pharmacogenomics is a rapidly evolving field with a strong foundation in basic science dating back to 1960. Pharmacogenomic findings have been translated into clinical care through collaborative efforts of clinical practitioners, pharmacists, clinical laboratories, and research groups. The methods used have transitioned from targeted genotyping of rel- atively few variants in individual genes to multiplexed multi-gene panels, and sequencing- based methods are likely on the horizon; however, no system exists for classifying and re- porting rare variants identified via sequencing-based approaches. Laboratory testing in pharmacogenomics is complex for several genes, including cytochrome P450 2D6 (CYP2D6), HLA-A, and HLA-B, owing to a high degree of polymorphisms, homology with other genes, and copy-number variation. These loci require specialized methods and famil- iarity with each gene, which may persist during the transition to next-generation sequenc- ing. Increasing implementation across laboratories and clinical facilities has required co- operative efforts to develop standard testing targets, nomenclature, and reporting prac- tices and guidelines for applying the results clinically. Beyond standardization, harmoniza- tion between pharmacogenomics and the broader field of genomic medicine may be es- sential for facilitating further adoption and realizing the full potential of personalized medi- cine. In this review, we describe the evolution of clinical laboratory testing for pharmacoge- nomics, including standardization efforts and the anticipated transition from targeted ge- notyping to sequencing-based pharmacogenomics. We speculate on potential upcoming developments, including pharmacoepigenetics, improved understanding of the impact of non-coding variants, use of large-scale functional genomics to characterize rare variants, and a renewed interest in polygenic risk or combinatorial approaches, which will drive the progression of the field.
Abstract
Pharmacogenomics is a rapidly evolving field with a strong foundation in basic science dating back to 1960. Pharmacogenomic findings have been translated into clinical care through collaborative efforts of clinical practitioners, pharmacists, clinical laboratories, and research groups. The methods used have transitioned from targeted genotyping of rel- atively few variants in individual genes to multiplexed multi-gene panels, and sequencing- based methods are likely on the horizon; however, no system exists for classifying and re- porting rare variants identified via sequencing-based approaches. Laboratory testing in pharmacogenomics is complex for several genes, including cytochrome P450 2D6 (CYP2D6), HLA-A, and HLA-B, owing to a high degree of polymorphisms, homology with other genes, and copy-number variation. These loci require specialized methods and famil- iarity with each gene, which may persist during the transition to next-generation sequenc- ing. Increasing implementation across laboratories and clinical facilities has required co- operative efforts to develop standard testing targets, nomenclature, and reporting prac- tices and guidelines for applying the results clinically. Beyond standardization, harmoniza- tion between pharmacogenomics and the broader field of genomic medicine may be es- sential for facilitating further adoption and realizing the full potential of personalized medi- cine. In this review, we describe the evolution of clinical laboratory testing for pharmacoge- nomics, including standardization efforts and the anticipated transition from targeted ge- notyping to sequencing-based pharmacogenomics. We speculate on potential upcoming developments, including pharmacoepigenetics, improved understanding of the impact of non-coding variants, use of large-scale functional genomics to characterize rare variants, and a renewed interest in polygenic risk or combinatorial approaches, which will drive the progression of the field.