The Association for Molecular Pathology (AMP) published consensus recommendations to aid in the design and validation of clinical genotyping assays that target chemotherapy toxicity concerning the dihydropyrimidine dehydrogenase (DPD) protein and the DPYD gene.
Mutations in DPYD (gene ID 1806) result in DPD deficiency, an error in pyrimidine metabolism associated with thymine-uraciluria, and an increased risk of toxicity in cancer patients receiving 5-fluorouracil (5-FU) chemotherapy, according to the U.S. National Institutes of Health, as of June 17.
The DPD protein is expressed in many tissues, with liver and peripheral blood having the highest expression levels and enzymatic activity, noted a related special article that was published on July 17 in the Journal of Molecular Diagnostics.
Victoria Pratt, PhD. Image courtesy of Indiana University.
"Testing for variants in the DPYD gene can help identify individuals who may be at increased risk for severe fluoropyrimidine-related toxicity," lead author Victoria Pratt, PhD, co-chair of the AMP PGx Working Group, said. Pratt is also the director of scientific affairs for pharmacogenetics at Agena Bioscience and an adjunct professor of clinical pharmacology at the Indiana University School of Medicine.
As of January 5, there were 122 clinical tests for DPYD from 47 laboratories worldwide listed in the Genetic Testing Registry, noted Pratt and colleagues as part of the joint consensus report from the AMP, the American College of Medical Genetics and Genomics, the Clinical Pharmacogenetics Implementation Consortium, the College of American Pathologists, the Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, the European Society for Pharmacogenomics and Personalized Therapy, the Pharmacogenomics Knowledgebase, and the Pharmacogene Variation Consortium.
Except for phenotyping tests (analyte or enzyme activity assays), all other clinical tests are molecular methods-based analyses of DPYD using targeted genotyping or sequencing. It is worthwhile, noting that gene copy number variation (CNV) analysis, i.e., testing for the presence of deletions and/or duplications, is included in 63/122 DPYD tests. In terms of test purpose, diagnosis (93 tests), screening (23), and drug response (19) are the three primary applications of DPYD testing, Pratt and colleagues noted.
"Some testing proponents have suggested the possibility of including DPYD when performing genomic analysis of tumors for other actionable therapeutic markers to detect patients at risk of toxicity to chemotherapeutic agents due to DPD deficiency," the authors noted.
The new DPYD report is the latest in a series of recommendations developed by the AMP PGx Working Group to help standardize clinical testing for frequently used genotyping assays, as well as to ensure that the appropriate variants are included in clinical pharmacogenetic (PGx) DPYD assays, according to AMP.
Points of interest include the following:
- Tier 1 and tier 2 variants and results
- Testing platforms
- Proficiency testing, or external quality assessment programs for DPYD genotyping
Over the past six years, AMP's PGx Working Group has developed a series of joint consensus guidelines to promote genotype concordance and test standardization between laboratories for the PGx assays most commonly used in clinical practice, stated Chair Dr. Karen Weck as part of AMP's announcement. Weck is also the director of molecular genetics and pharmacogenomics and a professor of pathology and laboratory medicine and genetics at the University of North Carolina at Chapel Hill.
The new report builds on AMP's earlier clinical genotyping recommendations for CYP3A4/CYP3A5, TPMT/NUDT15, CYP2D6, genes important for warfarin testing, CYP2C9, and CYP2C19. AMP's clinical DPYD PGx testing recommendations focus on clinical DPYD PGx testing that may be applied to all DPD-related medications, the report noted, adding that the consensus recommendations are not to be interpreted as prescriptive but to provide a reference guide.
