Dihydropyrimidine Dehydrogenase (DPYD), 3 Variants

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

• 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
  • 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
    • Approximately 25-50% 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

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