title: Promoter SNPs in G1/S checkpoint regulators and their impact on the susceptibility to childhood leukemia.
abstract: Mutations leading to the alteration of cell-cycle checkpoint functions are a common feature of most cancers. Because of the highly regulated nature of the cell cycle, it seems likely that variation in gene dosage of key components due to functional regulatory polymorphisms could play an important role in cancer development. Here we provide evidence of the involvement of promoter single-nucleotide polymorphisms (pSNPs) in the cyclin-dependent-kinase inhibitor genes CDKN2A, CDKN2B, CDKN1A, and CDKN1B in the etiology of childhood pre-B acute lymphoblastic leukemia (ALL). A case-control study, conducted in 240 patients with pre-B ALL and 277 healthy controls, combined with a family-based analysis using 135 parental trios, all of French-Canadian origin, were used to evaluate single-site genotypic as well as multilocus haplotypic associations for a total of 10 pSNPs. Using both study designs, we showed evidence of association between variants CDKN2A -222A, CDKN2B -593A, and CDKN1B -1608A, and an increased risk of ALL. These findings suggest that variable expression levels of cell-cycle inhibitor genes CDKN2A, CDKN2B, and CDKN1B due to regulatory polymorphisms could indeed influence the risk of childhood pre-B ALL and contribute to carcinogenesis.
authors.affiliation: Division of Hematology-Oncology, Research Centre, Centro Hospitalo-Universitaire Sainte-Justine, Montréal, QC, Canada, H3T 1C5.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Healy
authors.forename: Hélène
authors.initials: H
authors.lastname: Bélanger
authors.forename: Patrick
authors.initials: P
authors.lastname: Beaulieu
authors.forename: Mathieu
authors.initials: M
authors.lastname: Larivière
authors.forename: Damian
authors.initials: D
authors.lastname: Labuda
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnett
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics*; D005260:Female; D016193:G1 Phase; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016196:S Phase
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins