Discovery of novel mutations in the dihydropyrimidine dehydrogenase gene associated with toxicity of fluoropyrimidines and viewpoint on preemptive pharmacogenetic screening in patients. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Del Re, Marzia; Michelucci, Angela; Di Leo, Angelo; Cantore, Maurizio; Bordonaro, Roberto; Simi, Paolo; Danesi, Romano
• Is Part Of: EPMA journal. Volume 6:Issue 1(2015)
• Page Start: 1
• Page End: 5
• Publication Date: 2015-12
• Subjects: Prediction, Personalization, Medicine -- Toxicity -- Colorectal cancer -- Fluoropyrimidines -- DPD; Medicine, Preventive -- Periodicals; Diagnosis -- Periodicals; Medicine -- Periodicals; 616.075
• DOI: 10.1186/s13167-015-0039-x
• Languages: English
• ISSNs: 1878-5077

Abstract

Abstract 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 ofDPYD was performed on DNA extracted from peripheral blood. Results Three novel non-synonymous mutations ofDPYD, c.2509-2510insC, c.1801G>C, and c.680G>A, were detected in these subjects. Due to the absence of other deficient variants ofDPYD 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.