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DNA variants in region for noncoding interfering transcript of dihydrofolate reductase gene and outcome in childhood acute lymphoblastic leukemia.

Authors: Al-Shakfa, F  Dulucq, S  Brukner, I  Milacic, I  Ansari, M  Beaulieu, P  Moghrabi, A  Laverdiere, C  Sallan, SE  Silverman, LB  Neuberg, D  Kutok, JL  Sinnett, D  Krajinovic, M 
Citation: Al-Shakfa F, etal., Clin Cancer Res. 2009 Nov 15;15(22):6931-8. doi: 10.1158/1078-0432.CCR-09-0641. Epub 2009 Oct 27.
Pubmed: (View Article at PubMed) PMID:19861437
DOI: Full-text: DOI:10.1158/1078-0432.CCR-09-0641

PURPOSE: Dihydrofolate reductase (DHFR) is the major target of methotrexate, a key component in childhood acute lymphoblastic leukemia (ALL) treatment. We recently reported an association of DHFR promoter polymorphisms with ALL outcome. Lower event-free survival correlated with haplotype *1, defined by A(-317) and C(-1610) alleles. Haplotype *1 was also associated higher DHFR expression. EXPERIMENTAL DESIGN: Here, we analyzed adjacent 400-bp region participating in DHFR regulation as both a major promoter and a noncoding minor transcript. RESULTS: Six polymorphisms were identified, of which five were single nucleotide polymorphisms and one was length polymorphism composed of variable number of 9-bp elements and 9-bp insertion/deletion. Haplotype analysis including all promoter polymorphisms revealed diversification of haplotype *1 into five subtypes (*1a-*1e). DNA variations of major promoter/noncoding transcript region and haplotype *1 subtypes were subsequently analyzed for the association with ALL outcome. Lower event-free survival was associated with an A allele of G(308)A polymorphism (P = 0.02) and with *1b haplotype (P = 0.01). This association was particularly striking in high-risk patients (P = 0.001) and was subsequently confirmed in independent patient cohort (P = 0.02). Haplotype *1b was the only haplotype *1 subtype associated with higher mRNA levels. CONCLUSIONS: The study provides a new insight into DHFR regulatory variations predisposing to an event in ALL patients.


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CRRD Object Information
CRRD ID: 11039542
Created: 2016-03-07
Species: All species
Last Modified: 2016-03-07
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.