GENETIC TESTING OF THE DPYD GENE TO PREDICT TOXICITY IN PATIENTS TREATED WITH 5-FLUOROURACIL (5-FU) BASED CHEMOTHERAPY
The fluoropyrimidines 5-fluorouracil (5-FU) and capecitabine are widely used in the treatment of solid tumours. Approximately 10–40% of fluoropyrimidine-treated patients develop severe and sometimes life-threatening toxicity (neutropenia, nausea, vomiting, severe diarrhoea, stomatitis, mucositis, hand-foot syndrome) (Amstutz et al. 2018 Clinical Pharmacology and Therapeutics 103 (2): 210-216).
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. Numerous genetic variants in DPYD are known that alter the protein sequence or mRNA splicing. However, some decreased function DPYD variants are of primary relevance due to their population frequency, established impact on enzyme function and toxicity risk. Testing for the following variants is performed in the laboratory:
| Nucleotide change | Protein change | rsID | Haplotype name | Genomic coordinates (GRCh37) | Predicted DPD enzyme activity (%) |
| c.1905+1G>A | p.? |
rs3918290 | *2A | Chr1:g.97915614C>T | 0 |
| c.1679T>G | p.(Ile560Ser) | rs55886062 | *13 | Chr1:g.97981343A>C | 0 |
| c.2846A>T | p.(Asp949Val) | rs67376798 | Chr1:g.97547947T>A | 50 | |
|
c.1129–5923C>G c.1236G>A |
p.? p.(Glu412Glu) |
rs75017182 rs56038477 |
HapB3 |
Chr1:g.98045449G>C Chr1:g.98039419C>T |
50 |
Approximately 7% of Europeans carry at least one of the decreased function DPYD variants listed above. Of these variants, c.1905+1G>A and c.1679T>G have the most deleterious impact on DPD activity, whereas c.2846A>T and c.1129–5923C>G result in moderately reduced DPD activity.
Most other DPYD variants of phenotypic consequence are very rare (Amstutz et al. 2018 Clinical Pharmacology and Therapeutics 103 (2): 210-216). Please note that in individuals with African ancestry, the decreased function variant c.557A>G p.(Tyr186Cys) (previously described as rs115232898, p.Y186C) is relatively common (minor allele frequency 2%), testing for this variant is not currently performed on a routine basis. Please contact the laboratory if testing for the c.557A>G variant is required.
The laboratory participates in the European Molecular Genetics Quality Network (EMQN) sequencing scheme.
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