Clinical Information

5-Fluorouracil (5-FU) and its orally administered prodrug, capecitabine, are fluoropyrimidine-based chemotherapeutic agents that are widely used for the treatment of colorectal cancer and other solid tumors.

The dihydropyrimidine dehydrogenase (DPYD) gene encodes the rate-limiting enzyme for fluoropyrimidine catabolism and eliminates over 80% of administered 5-FU. Dihydropyrimidine dehydrogenase (DPYD) activity is subject to wide variability, mainly due to genetic variation.(table 1) This results in a broad range of enzymatic deficiency from partial (3%-5% of population) to complete loss (0.2% of population) of enzyme activity.(1,2) Patients who are deficient in DPYD are at an increased risk for side effects and toxicity when undergoing 5-FU treatment.(3) In addition, pathogenic homozygous or compound heterozygous variants within DPYD are associated with dihydropyrimidine dehydrogenase (DPD) deficiency. DPD deficiency shows large phenotypic variability, ranging from no symptoms to a convulsive disorder with motor and mental retardation.

The thymidine synthase (TYMS) enzyme catalyzes the transformation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (dTMP), essential for DNA replication, and is the main intracellular target of fluoropyrimidines. The promoter region of the thymidine synthase gene (TYMS) is polymorphic, containing both a 28-base pair tandem repeat and a single nucleotide polymorphism (table 1), each of which have been shown to influence the translation efficiency of TYMS mRNA. These variations may be associated with fluoropyrimidine toxicity and tumor response, although the literature is mixed in this regard.(4) The repeat is usually 2 or 3 28-base pair segments long (noted as 2R and 3R respectively) with 3R being considered wild type; and the single nucleotide polymorphism (SNP) occurs in the 12th base of the second repeat, when a 3R allele is present, and is noted as 3RG (wild type) or 3RC (when the SNP is present).

Table 1.  Known Genetic Variations Associated with Fluoropyrimidine Treatment

*Other or novel variations, besides those listed here, may also impact fluoropyrimidine related side effects and tumor response.

The DPYD gene is located on chromosome 1 and contains 2 transcripts. The longest transcript (NM_000110.3) contains 23 exons, and the shortest transcript (NM_001160301.1) contains 6 exons, with exon 6 being unique to this transcript. All exons (total of 24 from both transcripts), and exon-intron boundaries are assessed. The TYMS gene is located on chromosome 18 and contains 7 exons (transcript NM_001071.2). The 5' UTR region is assessed.

Genetic variations involved in the metabolic pathway of fluoropyrimidines have been shown to contribute to the differences in clinical outcomes including toxicity and tumor response.