Polymerase Chain Reaction (PCR)/Fluorescence Monitoring
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 Variant | Alternative Name(s) | Predicted Consequence in Patients Receiving 5-FU |
---|---|---|
c.1024G>A | rs183385770 | No DPD activity; increased toxicity risk |
c.1129-5923C>G | rs75017182 | Decreased DPD activity; increased toxicity risk |
c.1774C>T | rs59086055 | No DPD activity; increased toxicity risk |
c.2279C>T | rs112766203 | Decreased DPD activity; increased toxicity risk |
c.557A>G | rs115232898 | Decreased DPD activity; increased toxicity risk |
c.868A>G | rs146356975 | Decreased DPD activity; increased toxicity risk |
c.1679T>G | DPYD*13, rs55886062 | No DPD activity; increased toxicity risk |
c.1905+1G>A | DPYD*2A, rs3918290 | No DPD activity; increased toxicity risk |
c.2846A>T | rs67376798 | Decreased 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
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Fluorouracil therapy and DPYD genotype
Dean L, Kane M. Fluorouracil therapy and DPYD genotype. In: Pratt VM, Scott SA, Pirmohamed M, et al, eds. Medical Genetics Summaries. Bethesda, Maryland. Updated Jan 2021; accessed Aug 2024.
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PharmGKB - DPYD
PharmGKB. DPYD. Last updated 2024; accessed Feb 2025.
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PharmGKB-2024
PharmGKB. Last updated 2024; accessed Nov 2024.
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.