Dihydropyrimidine Dehydrogenase (DPYD), 3 Variants

Predict risk of dose-related toxicity to 5-FU therapy

Dihydropyrimidine dehydrogenase is an enzyme encoded by the DYPD gene and is responsible for the metabolism of 5-fluorouracil (5-FU), the most frequently used chemotherapeutic drug in the treatment of colorectal adenocarcinomas. Germline variants in DPYD affect enzyme production, which may result in dose-related toxicity or in a reduction of treatment effectiveness.

Disease Overview

Physiology

When 5-FU is metabolized in the body

  • ~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 ~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
    • Avoidance of fluoropyrimidine therapy is recommended
      •  An alternate drug should be selected
  • Heterozygous DYPD gene variants
    • Associated with 30-70% of normal DPD activity
    • Fluoropyrimidine therapy should be initiated with reduced dosing
      • ~50% of a standard dose is recommended
      • Titration of dose based on patient tolerability and therapeutic drug monitoring
  • Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing available at www.pharmgkb.org/gene/PA145

Genetics

Gene

DPYD

Variants Tested

DPYD Gene Variants
DPYD Variant Alternative Name(s) Predicted Consequence in Patients Receiving 5-FU

c.1679T>G

DPYD*13, rs55886062

Decreased DPD activity

Increased toxicity risk

c.1905+1G>A

DPYD*2A, IVS14+1 G>A, rs3918290

Abolished DPD activity

Greatly increased toxicity risk

c.2846A>T

rs67376798

Decreased DPD activity

Increased toxicity risk

See www.pharmgkb.org 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 alleles

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