Analysis of mutations and polymorphisms of dihydropyrimidine dehydrogenase (DPD) in prediction of toxicity caused by flouropyrimidines


Klin Onkol 2007; 20(2): 215-219.

Backgrounds: Development of serious toxicity during treatment with 5-fluorouracil (5FU) and its derivates is probably caused by impaired metabolic activities of the fluoropyrimidines’ catabolic enzymes. The crucial role in this pathway is played by rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD). Methods: We performed a mutation analysis in 31 patients with serious toxicity (Grade III-IV, NCIC CTC) following flouropyrimidine treatment, based on sequencing of cDNA derived from DPD mRNA. The characterized genetic alterations were screened via DHPLC analysis in a cohort of 21 patients with good fluoropyrimidine treatment tolerance (Grade 0-I; NCIC CTC) and in a panel of unselected population controls.
Results: We detected 8 different sequence variants – one splicing, 6 missense and one silent mutation. Except for the IVS14+1G>A (exon 14del) mutation found in 1/31 toxicity patients, and the newly characterized unclassified alteration c.187A>G (K63E), we have failed to find differences in frequency and type of mutations between fluoropyrimidine-treated patients with vs. without toxicity. Conclusion: Despite the high number of genetic alterations found in the DPYD gene we conclude that these could not explain the development of fluoropyrimidines toxicity in our population. Therefore, we think that currently the mutation analysis itself is not a predictive test for clinical assessment of patients at risk of 5FU toxicity development.