Discovery of novel mutations in the dihydropyrimidine dehydrogenase gene associated with toxicity of fluoropyrimidines and viewpoint on preemptive pharmacogenetic screening in patients

Background Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the metabolic pathway of 5-fluorouracil (5-FU) and other fluoropyrimidines to inactive compounds. For this reason, severe, life-threatening toxicities may occur in patients with deficient DPD activity when ad...

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Bibliographic Details
Published in:The EPMA journal 2015-09, Vol.6 (1), p.17, Article 17
Main Authors: Del Re, Marzia, Michelucci, Angela, Di Leo, Angelo, Cantore, Maurizio, Bordonaro, Roberto, Simi, Paolo, Danesi, Romano
Format: Article
Language:English
Subjects:
Biomedical and Life Sciences
Biomedicine
Colorectal cancer
Dehydrogenases
Enzymes
Fluorouracil
Genes
Genetic aspects
Health aspects
High performance liquid chromatography
Medicine/Public Health
Mutation
Pharmacogenetics
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Summary:Background Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the metabolic pathway of 5-fluorouracil (5-FU) and other fluoropyrimidines to inactive compounds. For this reason, severe, life-threatening toxicities may occur in patients with deficient DPD activity when administered standard doses of 5-FU and its prodrugs. Materials and methods We selected three patients with colorectal adenocarcinoma who displayed unexpected severe adverse reactions after treatment with 5-FU and capecitabine. To investigate the possible involvement of deficient variants of the DPD gene ( DPYD ), a denaturing HPLC (dHPLC) approach followed by target exon sequencing of DPYD was performed on DNA extracted from peripheral blood. Results Three novel non-synonymous mutations of DPYD , c.2509-2510insC, c.1801G>C, and c.680G>A, were detected in these subjects. Due to the absence of other deficient variants of DPYD and the compatibility of adverse reactions with fluoropyrimidine treatment, the novel variants were associated with a poor-metabolizer phenotype. Conclusions Stratification of patients on the basis of their genotype may help prevent toxicity, and the large body of evidence about the pathogenesis of fluoropyrimidine-induced adverse reactions strongly encourages the adoption of best practice recommendations to appropriately address this important clinical issue. This approach is of utmost importance within a preventive, prognostic, and personalized approach to patient care in the oncology setting.
ISSN:1878-5077
1878-5085
DOI:10.1186/s13167-015-0039-x