DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL.
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.
Dulucq
Stéphanie
S
Research Center, Centre Hospitalier Universitaire Mère-Enfant, Sainte-Justine, Department of Pediatrics, University of Montreal, QC, Canada.
St-Onge
Geneviève
G
Gagné
Vincent
V
Ansari
Marc
M
Sinnett
Daniel
D
Labuda
Damian
D
Moghrabi
Albert
A
Krajinovic
Maja
M
D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015996:Survival Rate; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D056741:Cyclin D; D016213:Cyclins; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D008727:Methotrexate