Promoter SNPs in G1/S checkpoint regulators and their impact on the susceptibility to childhood leukemia
Promoter SNPs in G1/S checkpoint regulators and their impact on the susceptibility to childhood leukemia
复制标题
DOI：
10.1182/blood-2006-02-003236
复制
发表时间：
2007-01-15
期刊：
影响因子：
20.3
通讯作者：
Sinnett, Daniel
中科院分区：
文献类型：
--
作者：
Healy, Jasmine;Belanger, Helene;Sinnett, Daniel
导致细胞周期检查点功能改变的突变是大多数癌症的共同特征。由于细胞周期的高度调控性质，功能调控多态性导致的关键成分基因剂量的变化似乎可能在癌症发展中发挥重要作用。在这里，我们提供了细胞周期蛋白依赖性激酶抑制剂基因 CDKN2A、CDKN2B、CDKN1A 和 CDKN1B 中的启动子单核苷酸多态性 (pSNP) 参与儿童前 B 期急性淋巴细胞白血病 (ALL) 病因学的证据。在 240 名 B ALL 患者和 277 名健康对照中进行的病例对照研究，结合使用 135 名法裔加拿大人的亲本三人组进行的基于家庭的分析，用于评估总共 10 个 pSNP 的单位点基因型以及多位点单倍型关联。使用这两种研究设计，我们显示了 CDKN1B -1608A 与 ALL 风险增加之间的关联证据。这些发现表明，由于调控多态性，细胞周期抑制剂基因 CDKN2A、CDKN2B 和 CDKN1B 的表达水平可变，确实可能影响儿童 pre-B ALL 的风险并导致致癌。变异 CDKN2A -222A、CDKN2B -593A 和 CDKN1B -1608A，以及 ALL 风险增加。这些发现表明，由于调控多态性，细胞周期抑制剂基因 CDKN2A、CDKN2B 和 CDKN1B 的表达水平可变，确实可能影响儿童 pre-B ALL 的风险并导致致癌。
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 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. 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.