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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7
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pubmed:dateCreated |
2008-3-25
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pubmed:abstractText |
Dihydrofolate reductase (DHFR) is the major target of methotrexate (MTX), a key component in childhood acute lymphoblastic leukemia (ALL) treatment. A total of 15 polymorphisms in DHFR promoter were analyzed, and 3 sites (C-1610G/T, C-680A, and A-317G) were identified as sufficient to define observed haplotypes (tag single nucleotide polymorphisms [tagSNPs]). These polymorphisms were investigated for association with treatment response in 277 children with ALL. Lower event-free survival (EFS) was associated with homozygosity for the allele A-317 and C-1610 (P=.03 and .02), and with the haplotype *1, defined by both C-1610 and A-317 alleles (P=.03). The haplotype *1 conferred higher transcriptional activity (P<.01 compared with haplotypes generating minimal luciferase expression). Quantitative mRNA analysis showed higher DHFR levels for particular haplotype *1 carriers (P<.01). The analysis combining haplotype *1 with thymidylate synthase (TS) and cyclin D1 (CCND1) genotypes previously shown to affect ALL outcome showed that the number of event-predisposing genotypes was associated with increasingly lower EFS (P<.001). In conclusion, DHFR promoter polymorphisms are associated with worse ALL outcome, likely due to a higher DHFR expression. Combined effects among genes of the folate cycle can further accentuate differences in the response to the treatment.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antimetabolites, Antineoplastic,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin D,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclins,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Neoplasm,
http://linkedlifedata.com/resource/pubmed/chemical/Folic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Methotrexate,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Neoplasm,
http://linkedlifedata.com/resource/pubmed/chemical/Tetrahydrofolate Dehydrogenase,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidylate Synthase
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0006-4971
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
111
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3692-700
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:18096764-Alleles,
pubmed-meshheading:18096764-Antimetabolites, Antineoplastic,
pubmed-meshheading:18096764-Cyclin D,
pubmed-meshheading:18096764-Cyclins,
pubmed-meshheading:18096764-DNA, Neoplasm,
pubmed-meshheading:18096764-Disease-Free Survival,
pubmed-meshheading:18096764-Female,
pubmed-meshheading:18096764-Folic Acid,
pubmed-meshheading:18096764-Haplotypes,
pubmed-meshheading:18096764-Humans,
pubmed-meshheading:18096764-Male,
pubmed-meshheading:18096764-Methotrexate,
pubmed-meshheading:18096764-Polymorphism, Single Nucleotide,
pubmed-meshheading:18096764-Precursor Cell Lymphoblastic Leukemia-Lymphoma,
pubmed-meshheading:18096764-Promoter Regions, Genetic,
pubmed-meshheading:18096764-RNA, Messenger,
pubmed-meshheading:18096764-RNA, Neoplasm,
pubmed-meshheading:18096764-Survival Rate,
pubmed-meshheading:18096764-Tetrahydrofolate Dehydrogenase,
pubmed-meshheading:18096764-Thymidylate Synthase,
pubmed-meshheading:18096764-Transcription, Genetic
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pubmed:year |
2008
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pubmed:articleTitle |
DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL.
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pubmed:affiliation |
Research Center, Centre Hospitalier Universitaire Mère-Enfant, Sainte-Justine, Department of Pediatrics, University of Montreal, QC, Canada.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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