DNA Variants in Region for Noncoding Interfering Transcript of Dihydrofolate Reductase Gene and Outcome in Childhood Acute Lymphoblastic Leukemia
| Autor: | Lewis B. Silverman, Daniel Sinnett, Stéphanie Dulucq, Ivan Brukner, Maja Krajinovic, Iva Milacic, Donna Neuberg, Albert Moghrabi, Caroline Laverdière, Fidaa Al-Shakfa, Marc Ansari, Stephen E. Sallan, Patrick Beaulieu, Jeffery L. Kutok |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male Cancer Research Single-nucleotide polymorphism Biology Cohort Studies Genetic variation Dihydrofolate reductase Humans Allele Child Promoter Regions Genetic Childhood Acute Lymphoblastic Leukemia Genetics Polymorphism Genetic Haplotype Case-control study Genetic Variation DNA Middle Aged Precursor Cell Lymphoblastic Leukemia-Lymphoma Molecular biology Tetrahydrofolate Dehydrogenase Methotrexate Haplotypes Oncology Pharmacogenetics Case-Control Studies biology.protein Female |
| Zdroj: | Clinical Cancer Research. 15:6931-6938 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-09-0641 |
| Popis: | 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 A317 and C1610 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 G308A 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. (Clin Cancer Res 2009;15(22):69318) |
| Databáze: | OpenAIRE |
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