PREDICTION OF 5-FLUOROURACIL TOXICITY

GENETIC TESTING OF THE DPYD GENE TO PREDICT TOXICITY IN PATIENTS TREATED WITH 5-FLUOROURACIL (5-FU) BASED CHEMOTHERAPY

5-fluorouracil is among the most commonly used chemotherapeutic agents for the treatment of solid carcinomas.  Up to 40% of patients develop severe to life-threatening toxicity from 5-FU.  Adverse events include neutropenic fever, anemia, thrombocytopenia, diarrhoea, nausea and vomiting (Loganayagam et al. 2010 Cancer Chemother Pharmacol 65:403-406). 

Dihydropyrimidine dehydrogenase (DPD) is involved in the catabolism of 5-FU.  Variants in the DPYD gene, which encodes DPD, result in wide inter-individual variation in DPD activity.  Patients with partial or complete DPD deficiency are more likely to suffer serious toxicity when exposed to fluoropyrimidines.  In the Northern European population, 3–5% are heterozygous with partial deficiency and 0.2% are homozygous with complete deficiency.  Four sequence variants, c.1905+1G>A, c.1679T>G (p.I560S), c.1601G>A (p.S534N) and c.2846A>T (p.D949V) are prevalent in the UK population and are significantly associated with grade 3-4 toxicity (Loganayagam et al. 2013 Br J Cancer 108:2505-2515).

The laboratory participates in the European Molecular Genetics Quality Network (EMQN) sequencing scheme.