Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5501141 | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2017 | 29 Pages |
Abstract
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Genetic variations in DPD have emerged as predictive risk factors for severe fluoropyrimidine toxicity. Here, we report novel and rare genetic variants underlying DPD deficiency in 9 cancer patients presenting with severe fluoropyrimidine-associated toxicity. All patients possessed a strongly reduced DPD activity, ranging from 9 to 53% of controls. Analysis of the DPD gene (DPYD) showed the presence of 21 variable sites including 4 novel and 4 very rare aberrations: 3 missense mutations, 2 splice-site mutations, 1 intronic mutation, a deletion of 21 nucleotides and a genomic amplification of exons 9-12. Two novel/rare variants (c.2843TÂ >Â C, c.321Â +Â 1GÂ >Â A) were present in multiple, unrelated patients. Functional analysis of recombinantly-expressed DPD mutants carrying the p.I948T and p.G284V mutation showed residual DPD activities of 30% and 0.5%, respectively. Analysis of a DPD homology model indicated that the p.I948T and p.G284V mutations may affect electron transfer and the binding of FAD, respectively. cDNA analysis showed that the c.321Â +Â 1GÂ >Â A mutation in DPYD leads to skipping of exon 4 immediately upstream of the mutated splice-donor site in the process of DPD pre-mRNA splicing. A lethal toxicity in two DPD patients suggests that fluoropyrimidines combined with other therapies such as radiotherapy might be particularly toxic for DPD deficient patients. Our study advocates a more comprehensive genotyping approach combined with phenotyping strategies for upfront screening for DPD deficiency to ensure the safe administration of fluoropyrimidines.
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Authors
André B.P. van Kuilenburg, Judith Meijer, Dirk Maurer, Doreen Dobritzsch, Rutger Meinsma, Maartje Los, Lia C. Knegt, Lida Zoetekouw, Rob L.H. Jansen, Vincent Dezentjé, Lieke H. van Huis-Tanja, Roel J.W. van Kampen, Jens Michael Hertz,