Promoter SNPs in G1/S checkpoint regulators and their impact on the susceptibility to childhood leukemia

Abstract

Mutations leading to the alteration of cellcycle 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 FrenchCanadian 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. (Blood. 2007;109:683-692)

A regulatory SNP at position −899 in CDKN1A is associated with systemic lupus erythematosus and lupus nephritis

“…15 The SNP change of C to A within the hexamer core of the Myb recognition element caused a dramatic decrease in gene expression in vivo. 16,17 On fusion of a promoter sequence from positions À2326 to þ 17 with C or A at À899 to the luciferase gene, the promoter sequence with the risk allele A displayed B15% lower activity than that with the non-risk allele C in both U937 (P ¼ 0.027) and HeLa (P ¼ 0.025) cells ( Figure 1).…”

Childhood cancer epidemiology in low‐income countries

“…14,15 Some other cases of childhood ALL can be attributed to maternal exposures during pregnancy, 16,17 in which risk may be modulated by genetic polymorphisms of enzyme systems responsible for the metabolism of drugs or environmental xenobiotics. [18][19][20][21] However, variations in environmental exposures and genetic susceptibility can only account for small differences in childhood leukemia incidence rates, and do not explain the large differences (up to 10-fold) between HIC and some LIC (Table 2). Hence, the role of underdiagnosis and underreporting must be investigated.…”

Transcriptional dysregulation during myeloid transformation in AML

“…Such an approach should also consider single-nucleotide polymorphisms in gene promoter sequences because of their quantitative impact on gene expression (Pastinen and Hudson, 2004;Healy et al, 2007). As is the case for the PU.1 gene, such regulatory regions can be far away from the coding sequences, and it will be a challenge to identify their roles in leukemia.…”