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.
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.
Authors: Torben S Mikkelsen; Caroline F Thorn; Jun J Yang; Cornelia M Ulrich; Deborah French; Gianluigi Zaza; Henry M Dunnenberger; Sharon Marsh; Howard L McLeod; Kathy Giacomini; Mara L Becker; Roger Gaedigk; James Steven Leeder; Leo Kager; Mary V Relling; William Evans; Teri E Klein; Russ B Altman Journal: Pharmacogenet Genomics Date: 2011-10 Impact factor: 2.089
Authors: Julie Rousseau; Vincent Gagné; Malgorzata Labuda; Cyrielle Beaubois; Daniel Sinnett; Caroline Laverdière; Albert Moghrabi; Stephen E Sallan; Lewis B Silverman; Donna Neuberg; Jeffery L Kutok; Maja Krajinovic Journal: Blood Date: 2011-10-04 Impact factor: 22.113
Authors: Mikhail Ponomarenko; Dmitry Rasskazov; Olga Arkova; Petr Ponomarenko; Valentin Suslov; Ludmila Savinkova; Nikolay Kolchanov Journal: Biomed Res Int Date: 2015-10-04 Impact factor: 3.411
Authors: Mikhail P Ponomarenko; Olga Arkova; Dmitry Rasskazov; Petr Ponomarenko; Ludmila Savinkova; Nikolay Kolchanov Journal: Front Immunol Date: 2016-04-04 Impact factor: 7.561