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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3692-3700.
Prepublished online as a Blood First Edition Paper on December 20, 2007; DOI 10.1182/blood-2007-09-110593.

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NEOPLASIA

DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL

Stéphanie Dulucq1, Geneviève St-Onge1, Vincent Gagné1, Marc Ansari1, Daniel Sinnett1,2, Damian Labuda1,2, Albert Moghrabi1,2, and Maja Krajinovic1,3

1 Research Center, Centre Hospitalier Universitaire Mère-Enfant, Sainte-Justine, Montreal; and 2 Department of Pediatrics, and 3 Department of Pharmacology, University of Montreal, Montreal, QC

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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