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Clinical Implications of Dihydropyrimidine Dehydrogenase (DPD) Deficiency in Patients with Severe 5-Fluorouracil-associated Toxicity: Identification of New Mutations in the DPD Gene

Academic Medical Center, University of Amsterdam, Emma Children’s Hospital and Department of Clinical Chemistry, 1100 DE Amsterdam [A. B. P. v. K., J. H., D. J. R., L. Z., H. V. L., P. V., A. H. v. G.]; University Hospital St. Radboud, Department of Pediatrics, 6500 HB Nijmegen [R. A. D. A.]; and Hospital Meppel-Hoogeveen, 7940 AM Meppel [J. G. M.], the Netherlands

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU), and it is suggested that patients with a partial deficiency of this enzyme are at risk for developing a severe 5FU-associated toxicity. To evaluate the importance of this specific type of inborn error of pyrimidine metabolism in the etiology of 5FU toxicity, an analysis of the DPD activity, the DPD gene, and the clinical presentation of patients suffering from severe toxicity after the administration of 5FU was performed. Our study demonstrated that in 59% of the cases, a decreased DPD activity could be detected in peripheral blood mononuclear cells. It was observed that 55% of patients with a decreased DPD activity suffered from grade IV neutropenia compared with 13% of patients with a normal DPD activity (P = 0.01). Furthermore, the onset of toxicity occurred, on average, twice as fast in patients with low DPD activity as compared with patients with a normal DPD activity (10.0 ± 7.6 versus 19.1 ± 15.3 days; P < 0.05). Analysis of the DPD gene of 14 patients with a reduced DPD activity revealed the presence of mutations in 11 of 14 patients, with the splice site mutation IVS14+1GA being the most abundant one (6 of 14 patients; 43%). Two novel missense mutations 496AG (M166V) and 2846AT (D949V) were detected in exon 6 and exon 22, respectively. Our results demonstrated that at least 57% (8 of 14) of the patients with a reduced DPD activity have a molecular basis for their deficient phenotype.

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