5-Fluorouracil (5FU) is a fluorinated pyrimidine analogue commonly used in combination chemotherapy regimens for patients with breast, colorectal, lung, and other malignancies. Dihydropyrimidine dehydrogenase (DPD), an enzyme encoded by the DPYD gene, is the rate-limiting step in pyrimidine catabolism and deactivates more than 80% of standard doses of 5FU and the oral 5FU prodrug capecitabine.
True deficiency of DPD affects approximately 5% of the overall population. In these patients, the lack of enzymatic activity increases the half-life of the drug, resulting in excess drug accumulation and toxicity.
In addition, 3% to 5% of the population has a partial DPD deficiency due to sequence variations in DPYD gene, which potentially limits their ability to fully metabolize the drug, thereby resulting in toxicity.
The IVS14+1G>A mutation in intron 14 coupled with exon 14 deletion (known as DPYD*2A) is the most well known variant resulting in partial DPD deficiency and 5FU toxicity.
Other recognized variants associated with toxicity include 496A>G in exon 6; 2846A>T in exon 22;
and T1679G (DPYD*13) in exon 13,
although multiple other mutations have been detected in individual families and via full gene sequences.