5-Fluorouracil Sensitivity

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Predict toxicity and responsiveness of tumor to 5-fluorouracil (5-FU) therapy

Laboratory Testing

  • Molecular testing​
    • DPYD variants and TYMS gene mutations testing – may help to predict responsiveness to 5-FU therapy (see table in Background for predicted consequences of specific mutations)

5-fluorouracil (5-FU) is a fluoropyrimidine drug and the most frequently used chemotherapeutic in the treatment of colorectal cancer. Genetic variants in the DPYD and mutations in TYMS genes may predict the risk of 5-FU toxicity, responsiveness to 5-FU therapy, and clinical outcome to aid in patient care.

Genetics and Epidemiology

Pathophysiology

  • Dihydropyrimidine dehydrogenase (DPD) enzyme – encoded by DPYD gene
    • Catabolizes >80% of 5-FU into an inactive form that is eliminated in the urine (rate limiting enzyme)
    • Reduced DPD activity can lead to the accumulation of active 5-FU metabolite, increasing the risk for 5-FU toxicity
  • Thymidylate synthase (TYMS) enzyme – encoded by TYMS gene
    • Primary target for 5-FU
      • Remaining 5-FU drug is metabolized by different enzymes into an active form that inhibits the synthesis of DNA and RNA by competitive inhibition of TYMS or by direct incorporation of cytotoxic metabolites into nucleic acids
    • TYMS gene mutations result in reduced expression of TYMS and may be associated with higher clinical responsiveness to 5-FU therapy and increased risk of toxicity

Clinical Presentation

  • Grade III-IV toxicity – may occur if mutations change enzyme activity
    • Mucositis
    • Neutropenia
    • Nausea
    • Diarrhea
    • Neurological symptoms
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

5-Fluorouracil (5-FU) Toxicity and Chemotherapeutic Response, 5 Mutations 2007228
Method: Polymerase Chain Reaction/Single Nucleotide Extensions/Fragment Analysis

Limitations 

Only targeted mutations in the DPYD and TYMS genes are evaluated

Rare diagnostic errors may occur due to rare sequence variations

Genetic and/or non-genetic factors that are not detected by this assay may affect 5-FU drug metabolism, efficacy, and risk for toxicity

Genotyping does not replace the need for therapeutic drug monitoring or clinical observation

Lack of detection of the targeted DPYD and TYMS mutations does not rule out risk for 5-FU toxicity or predict degree of responsiveness to 5-FU

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

Limitations 

Only targeted variants in DPYD gene will be detected

Rare diagnostic errors may occur due to rare sequence variations

Genetic and/or non-genetic factors that are not detected by this assay may affect 5-FU drug metabolism, efficacy, and risk for toxicity

Genotyping does not replace the need for therapeutic drug and clinical monitoring

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

Guidelines

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

General References

Amstutz U, Froehlich TK, Largiadèr CR. Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity. Pharmacogenomics. 2011; 12(9): 1321-36. PubMed

Lee S, McLeod HL. Pharmacogenetic tests in cancer chemotherapy: what physicians should know for clinical application. J Pathol. 2011; 223(1): 15-27. PubMed

Ren D, Kim I, Koh SB, Chang SJ, Eom M, Yi SY, Seong SH, Kim M, Bronner MP, Cho M. Comparative analysis of thymidylate synthase at the protein, mRNA, and DNA levels as prognostic markers in colorectal adenocarcinoma. J Surg Oncol. 2009; 100(7): 546-52. PubMed

Medical Reviewers

Last Update: August 2016