Submitted February 10, 2006
Accepted August 30, 2006
Promoter SNPs in G1/S checkpoint regulators and their impact on the susceptibility to childhood leukemia
Jasmine Healy, Helene Belanger, Patrick Beaulieu, Mathieu Lariviere, Damian Labuda, and Daniel Sinnett*
Division of Hematology-Oncology, Research Centre, Sainte-Justine Hospital, Montreal (Quebec), Canada
Department of Pediatrics, University of Montreal, Montreal (Quebec), Canada
* Corresponding author; email: daniel.sinnett{at}umontreal.ca.
Mutations leading to 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 SNPs (pSNPs) in 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 pre-B ALL patients 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 ten 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.
