CHEK2 variant 1157T may be associated with increased breast cancer risk
CHEK2 variant 1157T may be associated with increased breast cancer risk
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DOI：
10.1002/ijc.20299
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发表时间：
2004-09-10
影响因子：
6.4
通讯作者：
Nevanlinna, H
中科院分区：
文献类型：
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作者：
Kilpivaara, O;Vahteristo, P;Nevanlinna, H
细胞周期检查点激酶 2 (CHEK2) 是细胞对 DNA 损伤反应的传感器。 CHEK2 1100delC 此前已被证明是一种低外显率乳腺癌易感性等位基因。我们评估了该基因 FHA 结构域中的另一种 CHEK2 变体 1157T 与乳腺癌的关联。在基于人群的乳腺癌患者系列中发现 1157T 的频率显着高于人群对照 (100/1885, 5.3%) (77/1035, 7.4%, 比值比 [OR] = 1.43, 95% 置信区间 [CI] = 1.06-1.95, p = 0.021)。家族性乳腺癌患者的发病率并未升高（28/507，5.5%，OR = 1.04，95% CI = 0.68-1.61）。 1157T 蛋白破坏细胞对电离辐射的反应，并显示体内底物识别缺陷，在肿瘤组织和培养细胞中以正常水平表达。 1157T 蛋白是稳定的，并且与在人类细胞中共表达的野生型 CHEK2 形成二聚体。 1157T 蛋白的这些功能特性表明，该变体可能通过与野生型 CHEK2 形成异二聚体，对杂合载体细胞中的正常 CHEK2 蛋白池产生负面影响。 1157T 变异可能与乳腺癌风险相关，但风险低于 1100delC。 (C) 2004 Wiley-Liss, Inc.
Cell cycle checkpoint kinase 2 (CHEK2) is a transducer of cellular responses to DNA damage. The CHEK2 1100delC has previously been shown to be a low-penetrance breast cancer susceptibility allele. We have evaluated the role of another CHEK2 variant, 1157T in the FHA domain of the gene, for association with breast cancer. 1157T was found at a significantly higher frequency in the population-based series of breast cancer patients (77/1035, 7.4%, odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.06-1.95, p = 0.021) than among population controls (100/1885, 5.3%). The frequency in the familial breast cancer patients was not elevated (28/507, 5.5%, OR = 1.04, 95% CI = 0.68-1.61). The 1157T protein, that undermines cellular responses to ionizing radiation and shows deficiency in substrate recognition in vivo, was expressed at normal level in tumor tissues as well as in cultured cells. The 1157T protein was stable and it dimerized with the wild-type CHEK2 co-expressed in human cells. These functional properties of the 1157T protein suggest that this variant may have negative effect on the pool of normal CHEK2 protein in heterozygous carrier cells by formation of heterodimers with wild-type CHEK2. The 1157T variant may be associated with breast cancer risk, but the risk is lower than for 1100delC. (C) 2004 Wiley-Liss, Inc.