Source:http://linkedlifedata.com/resource/pubmed/id/20803296
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
5
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| pubmed:dateCreated |
2010-10-15
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| pubmed:abstractText |
Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme acting in the catabolism of the widely used antineoplastic agent 5-fluorouracil (5FU). DPD deficiency is known to cause a potentially lethal toxicity following administration of 5FU. Here, we report novel genetic mechanisms underlying DPD deficiency in patients presenting with grade III/IV 5FU-associated toxicity. In one patient a genomic DPYD deletion of exons 21-23 was observed. In five patients a deep intronic mutation c.1129-5923C>G was identified creating a cryptic splice donor site. As a consequence, a 44 bp fragment corresponding to nucleotides c.1129-5967 to c.1129-5924 of intron 10 was inserted in the mature DPD mRNA. The deleterious c.1129-5923C>G mutation proved to be in cis with three intronic polymorphisms (c.483 + 18G>A, c.959-51T>G, c.680 + 139G>A) and the synonymous mutation c.1236G>A of a previously identified haplotype. Retrospective analysis of 203 cancer patients showed that the c.1129-5923C>G mutation was significantly enriched in patients with severe 5FU-associated toxicity (9.1%) compared to patients without toxicity (2.2%). In addition, a high prevalence was observed for the c.1129-5923C>G mutation in the normal Dutch (2.6%) and German (3.3%) population. Our study demonstrates that a genomic deletion affecting DPYD and a deep intronic mutation affecting pre-mRNA splicing can cause severe 5FU-associated toxicity. We conclude that screening for DPD deficiency should include a search for genomic rearrangements and aberrant splicing.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antimetabolites, Antineoplastic,
http://linkedlifedata.com/resource/pubmed/chemical/Dihydrouracil Dehydrogenase (NADP),
http://linkedlifedata.com/resource/pubmed/chemical/Fluorouracil,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger
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| pubmed:status |
MEDLINE
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| pubmed:month |
Nov
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| pubmed:issn |
1432-1203
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| pubmed:author |
pubmed-author:DerleynVeerle AVA,
pubmed-author:DobritzschDoreenD,
pubmed-author:Etienne-GrimaldiMarie-ChristineMC,
pubmed-author:GrossEvaE,
pubmed-author:HennekamRaoul C MRC,
pubmed-author:KiechleMarionM,
pubmed-author:KlümpenHeinz-JosefHJ,
pubmed-author:MaartenseEdE,
pubmed-author:MannensMarcel M A MMM,
pubmed-author:MaringJan GerardJG,
pubmed-author:MeijerJudithJ,
pubmed-author:MeinsmaRutgerR,
pubmed-author:MilanoGérardG,
pubmed-author:MulAdri N P MAN,
pubmed-author:SchmidVeronikaV,
pubmed-author:VijzelaarRaymonR,
pubmed-author:van KuilenburgAndré B PAB
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| pubmed:issnType |
Electronic
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| pubmed:volume |
128
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| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
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| pubmed:pagination |
529-38
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| pubmed:dateRevised |
2010-11-1
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| pubmed:meshHeading |
pubmed-meshheading:20803296-Adult,
pubmed-meshheading:20803296-Aged,
pubmed-meshheading:20803296-Antimetabolites, Antineoplastic,
pubmed-meshheading:20803296-Comparative Genomic Hybridization,
pubmed-meshheading:20803296-Dihydrouracil Dehydrogenase (NADP),
pubmed-meshheading:20803296-Female,
pubmed-meshheading:20803296-Fluorouracil,
pubmed-meshheading:20803296-Gene Rearrangement,
pubmed-meshheading:20803296-Humans,
pubmed-meshheading:20803296-Introns,
pubmed-meshheading:20803296-Male,
pubmed-meshheading:20803296-Middle Aged,
pubmed-meshheading:20803296-Mutation, Missense,
pubmed-meshheading:20803296-Polymerase Chain Reaction,
pubmed-meshheading:20803296-Polymorphism, Genetic,
pubmed-meshheading:20803296-RNA, Messenger,
pubmed-meshheading:20803296-RNA Splicing,
pubmed-meshheading:20803296-Sequence Analysis, DNA,
pubmed-meshheading:20803296-Sequence Deletion
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| pubmed:year |
2010
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| pubmed:articleTitle |
Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity.
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| pubmed:affiliation |
Department of Clinical Chemistry, Academic Medical Center, Emma Children's Hospital, University of Amsterdam, Amsterdam, The Netherlands. a.b.vanKuilenburg@amc.uva.nl
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| pubmed:publicationType |
Journal Article
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