Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the breakdown of the chemotherapeutic agent 5-fluorouracil (5-FU) and its prodrugs. Approximately 80% of the administered 5-FU dose is metabolized via DPD. Various variants in the DPYD gene can lead to DPD deficiency, which limits the metabolism of DPD substrates. Patients with pathogenic variants in the DPYD gene have an increased risk of developing severe toxicities during 5-FU therapy. In addition to the well-characterized exon 14 skipping mutation (DPYD*2A, rs3918290), other variants in the DPD gene have also been associated with 5-FU toxicity. DPYD genotyping can help reduce the risk of serious side effects during 5-FU therapy.
The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recommends that patients be tested for the absence or partial deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD) before beginning cancer treatment with fluorouracil-containing drugs administered by injection or infusion (source: German Federal Institute for Drugs and Medical Devices, BfArM). It is recommended to test for the exon 14 skipping mutation c.1905+1G>A, as well as the variants c.1129-5923C>G (Haplotype B), c.1679T>G (DPYD*13, exon 13), and c.2846A>T (exon 22). These recommendations are also in line with the current guidelines issued by CPIC and DPWG.
Detailed information on toxicity symptoms and DPD enzyme deficiency can also be found in the safety warnings of the product information, the Clinical Pharmacogenetics Implementation Consortium (CPIC®) and the Dutch Pharmacogenetics Working Group (DPWG) guidelines, as well as in the DGHO position paper [in German] on fluorouracil and DPYD.
It is important to note that a negative result in genetic testing cannot completely rule out DPD deficiency, as there are additional known variants in the gene that are associated with reduced enzyme activity, but whose clinical significance is currently unclear.
Note: Combined heterozygosity or homozygosity for certain pathogenic variants in the DPYD gene may lead to the clinical presentation of hereditary thymine-uraciluria or familial pyrimidinemia.
References
Red Hand Letter on medicinal products containing 5-fluorouracil (i.v.), capecitabine and tegafur: Pre-treatment testing to identify patients with DPD deficiency. Dated 04.06.2020 [in German].
Wörmann et al. 2020, Positionspapier zur DPD-Testung, DGHO / Lunenburg et al. 2020, Eur J Hum Genet 28: 508–517 / Caudle et al. 2013, CPIC guidelines, Clin Pharmacol Ther 94:640 / Saif 2013, Cancer Genomics Proteomics, 10:89 / Fachinformation FLUOROURACIL-GRY® / Swen et al. 2011, Clin Pharmacol Ther 89:662
