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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
DNA variants in region for noncoding interfering transcript of Dihydrofolate reductase gene and outcome in childhood acute lymphoblastic leukemia
Clinical Cancer Research, Volume 15, No. 22, Year 2009
Notification
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Description
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 intofive 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 308A 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. © 2009 American Association for Cancer Research.
Authors & Co-Authors
Al-Shakfa, Fidaa
Canada, Montreal
Chu Sainte-justine - le Centre Hospitalier Universitaire Mère-enfant
Canada, Montreal
University of Montreal
Dulucq, Stéphanie
Canada, Montreal
Chu Sainte-justine - le Centre Hospitalier Universitaire Mère-enfant
Brukner, Ivan
Canada, Montreal
Chu Sainte-justine - le Centre Hospitalier Universitaire Mère-enfant
Milacic, Iva
Canada, Montreal
Chu Sainte-justine - le Centre Hospitalier Universitaire Mère-enfant
Ansari, Marc
Canada, Montreal
Chu Sainte-justine - le Centre Hospitalier Universitaire Mère-enfant
Beaulieu, Patrick
Canada, Montreal
Chu Sainte-justine - le Centre Hospitalier Universitaire Mère-enfant
Moghrabi, Albert
Canada, Montreal
Chu Sainte-justine - le Centre Hospitalier Universitaire Mère-enfant
Canada, Montreal
University of Montreal
Laverdière, Caroline
Canada, Montreal
Chu Sainte-justine - le Centre Hospitalier Universitaire Mère-enfant
Canada, Montreal
University of Montreal
Sallan, Stephen E.
United States, Boston
Dana-farber Cancer Institute
South Africa, Rondebosch
Children's Hospital
Silverman, Lewis B.
United States, Boston
Dana-farber Cancer Institute
South Africa, Rondebosch
Children's Hospital
Neuberg, Donna S.
United States, Boston
Dana-farber Cancer Institute
Kutok, Jeffery L.
United States, Boston
Brigham and Women's Hospital
Sinnett, Daniel
Canada, Montreal
Chu Sainte-justine - le Centre Hospitalier Universitaire Mère-enfant
Canada, Montreal
University of Montreal
Krajinovic, Maja
Canada, Montreal
Chu Sainte-justine - le Centre Hospitalier Universitaire Mère-enfant
Canada, Montreal
University of Montreal
Statistics
Citations: 39
Authors: 14
Affiliations: 5
Identifiers
Doi:
10.1158/1078-0432.CCR-09-0641
ISSN:
10780432
Research Areas
Cancer
Genetics And Genomics
Health System And Policy
Maternal And Child Health
Study Design
Cohort Study