Dihydropyrimidine Dehydrogenase (DPYD)

Last Literature Review: April 2019 Last Update:

The test predicts risk of dose-related toxicity to 5-FU therapy.

For more information about combined DPYD and UGT1A1 testing, refer to the Dihydropyrimidine Dehydrogenase (DPYD) and UPD Glucuronosyltransferase 1A1 (UGT1A1) Genotyping Test Fact Sheet.

Dihydropyrimidine dehydrogenase, an enzyme encoded by the DPYD gene, is responsible for metabolizing 5-fluorouracil (5-FU), a chemotherapeutic drug frequently used to treat many types of cancer, including colorectal adenocarcinomas. Germline variants in DPYD affect enzyme production, which may result in dose-related toxicity or in a reduction of treatment effectiveness. 

For more information on pharmacogenetic testing, refer to the ARUP Consult Germline Pharmacogenetics - PGx topic.
 

Disease Overview

Physiology

When 5-FU is metabolized in the body

  • Approximately 80% is catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD) into an inactive form, dihydro 5-FU, and excreted in urine
  • Remaining drug is metabolized into an active form which inhibits the synthesis of both DNA and RNA by
    • Direct incorporation of cytotoxic metabolites (5-FUTP and 5-FdUTP) into nucleic acids
    • Competitive inhibition of the thymidylate synthase (TYMS) enzyme

Treatment Issues

  • Intravenous 5-FU: Adrucil (5-fluorouracil)
  • Oral 5-FU prodrugs: Xeloda (capecitabine), Uftoral (tegafur/uracil)
  • Grade III-IV drug toxicity attributed to 5-FU occurs in approximately 16% of individuals
  • Germline variants in the DPYD gene can lead to reduced 5-FU catabolism and result in grade III-IV 5-FU toxicity
    • Complications include hematologic, gastrointestinal, and dermatologic symptoms as well as toxicity-related death
    • Clinical testing for variants that alter 5-FU metabolism may aid in patient care

Clinical Issues (5-FU Dosing)

  • Homozygous or compound heterozygous DYPD gene variants
    • Associated with DPD enzyme deficiency
  • Heterozygous DYPD gene variants
    • Associated with 30-70% of normal DPD activity
  • Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing available at PharmGKB 

Genetics

Gene

DPYD

Variants Tested

DPYD Gene Variants
DPYD VariantAlternative Name(s)Predicted Consequence in Patients Receiving 5-FU
c.1024G>Ars183385770No DPD activity; increased toxicity risk
c.1129-5923C>Grs75017182Decreased DPD activity; increased toxicity risk
c.1774C>Trs59086055No DPD activity; increased toxicity risk
c.2279C>Trs112766203Decreased DPD activity; increased toxicity risk
c.557A>Grs115232898Decreased DPD activity; increased toxicity risk
c.868A>Grs146356975Decreased DPD activity; increased toxicity risk
c.1679T>GDPYD*13, rs55886062No DPD activity; increased toxicity risk
c.1905+1G>ADPYD*2A, rs3918290No DPD activity; increased toxicity risk
c.2846A>Trs67376798Decreased DPD activity; increased toxicity risk

See PharmGKB  for allele frequency and other data about these variants.

Test Interpretation

Results

Positive

  • DPYD gene variant detected
    • Predicts decreased DPD enzymatic activity
    • Associated with an increased risk for grade III-IV 5-FU toxicity

Negative

  • No variants detected in DPYD: predictive of *1 functional allele

Limitations

  • Only targeted variants in the DPYD gene will be detected
  • Rare diagnostic errors may occur due to rare sequence variations
  • Genetic and/or nongenetic factors not detected by this test may affect 5-FU drug metabolism and efficacy and the risk for toxicity
  • Genotyping does not replace the need for therapeutic drug monitoring or clinical observation
  • Lack of detection of the targeted DPYD variants does not rule out risk for 5-FU toxicity or predict degree of responsiveness to 5-FU

References