Dihydropyrimidine Dehydrogenase (DPYD), 3 Variants

Dihydropyrimidine Dehydrogenase (DPYD), 3 Variants 2012166
Method: Polymerase Chain Reaction/Fluorescence Monitoring

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 
  1. Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M. Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther. 2013; 94(6): 640-5. PubMed

Last Update: May 2019