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Severe fluoropyrimi...
Severe fluoropyrimidine toxicity due to novel and rare DPYD missense mutations, deletion and genomic amplification affecting DPD activity and mRNA splicing
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van Kuilenburg, André B P (författare)
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Meijer, Judith (författare)
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- Maurer, Dirk, 1985- (författare)
- Uppsala universitet,Biokemi,Dobritzsch
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- Dobritzsch, Doreen, 1972- (författare)
- Uppsala universitet,Biokemi,Dobritzsch
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Meinsma, Rutger (författare)
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Los, Maartje (författare)
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Knegt, Lia C (författare)
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Zoetekouw, Lida (författare)
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Jansen, Rob L H (författare)
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Dezentjé, Vincent (författare)
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van Huis-Tanja, Lieke H (författare)
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van Kampen, Roel J W (författare)
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Hertz, Jens Michael (författare)
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Hennekam, Raoul C M (författare)
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(creator_code:org_t)
- Elsevier BV, 2017
- 2017
- Engelska.
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Ingår i: Biochimica et Biophysica Acta. - : Elsevier BV. - 0006-3002 .- 1878-2434. ; 1863:3, s. 721-730
- Relaterad länk:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.2843T>C, c.321+1G>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.321+1G>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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Nyckelord
- Dihydropyrimidine dehydrogenase
- DPYD
- 5-Fluorouracil
- Capecitabine
- Pharmacogenetics
- Toxicity
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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- Av författaren/redakt...
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van Kuilenburg, ...
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Meijer, Judith
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Maurer, Dirk, 19 ...
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Dobritzsch, Dore ...
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Meinsma, Rutger
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Los, Maartje
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visa fler...
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Knegt, Lia C
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Zoetekouw, Lida
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Jansen, Rob L H
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Dezentjé, Vincen ...
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van Huis-Tanja, ...
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van Kampen, Roel ...
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Hertz, Jens Mich ...
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Hennekam, Raoul ...
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visa färre...
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- MEDICIN OCH HÄLSOVETENSKAP
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Biochimica et Bi ...
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Biochimica et Bi ...
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Uppsala universitet