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

EPMA Journal

Romano Danesi³  Paolo Simi⁴  Roberto Bordonaro¹  Maurizio Cantore⁵  Angelo Di Leo²  Angela Michelucci⁴  Marzia Del Re³ 

[1] Medical Oncology Unit, Azienda Ospedaliera Garibaldi, Catania, Italy;Medical Oncology Unit, ASL4, Prato, Italy;Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, 55, Via Roma, Pisa, 56126, Italy;Cytogenetics and Molecular Genetics Unit, University Hospital, Pisa, Italy;Medical Oncology Unit, Azienda Ospedaliera Carlo Poma, Mantova, Italy

关键词: DPD;    Fluoropyrimidines;    Colorectal cancer;    Toxicity;    Prediction, Personalization, Medicine;   

Others  :  1224076
DOI  :  10.1186/s13167-015-0039-x

 received in 2015-07-30, accepted in 2015-08-09,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Del Re et al.

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