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Example clinical scenario

A 57-year-old male with metastatic hepatocellular carcinoma is considered for treatment with palliative combination chemotherapy including 5-fluorouracil. Constitutional (germline) DPYD testing shows a pathogenic variant.

Impact of the genomic result

  • DPYD encodes the enzyme dihydropyrimidine dehydrogenase (DPD), which is required for effective metabolism of fluoropyrimidine-based chemotherapies.
  • Patients with constitutional (germline) pathogenic variants in the DPYD gene have DPD deficiency, which means that they cannot metabolise fluoropyrimidine as efficiently as individuals with wild-type DPYD. This results in serious and sometimes life-threatening toxicity, including diarrhoea, mucositis and skin reactions, if fluoropyrimidine chemotherapy is given at standard doses.

What do you need to do?

Management of the current cancer

  • Fluorouracil is a fluoropyrimidine chemotherapy drug that may be used as a palliative systemic anti-cancer therapy for advanced hepatocellular cancer.
  • Depending on the DPYD variants identified and the associated reduction in DPYD activity, either:
    • the fluoropyrimidine chemotherapy (fluorouracil or capecitabine) is commenced at a reduced dose (the dose may be increased for the second cycle and subsequent cycles according to tolerance of the first cycle); or
    • an alternative treatment is used.
  • Full details of recommended dosing adjustments are provided by the UK Chemotherapy Board.
  • DPD deficiency may arise as a consequence of heterozygous (monoallelic) or compound heterozygous or homozygous (biallelic) DPYD pathogenic variants.
  • Individuals with biallelic DPYD variants (autosomal recessive DPD deficiency) are variably affected. Most remain asymptomatic, other than having an increased sensitivity to fluoropyrimidines, but some demonstrate serious problems (including seizures, developmental delay, hypotonia and microcephaly), which can manifest any time from birth.
  • Cascade testing of the patient’s family members is not usually required, as all patients being considered for fluoropyrimidine chemotherapy should now undergo DPYD testing prior to commencing treatment. It is good practice for patients to make relatives aware of their diagnosis, however, particularly in the context of inherited cancer susceptibility syndromes.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.


For clinicians


For patients

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  • Last reviewed: 19/02/2024
  • Next review due: 19/02/2025
  • Authors: Dr Ellen Copson
  • Reviewers: Dr Terri McVeigh