A novel recurrent CHEK2 Y390C mutation identified in high-risk Chinese breast cancer patients impairs its activity and is associated with increased breast cancer risk
A novel recurrent CHEK2 Y390C mutation identified in high-risk Chinese breast cancer patients impairs its activity and is associated with increased breast cancer risk
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在中国高危乳腺癌患者中发现的一种新的复发性 CHEK2 Y390C 突变会损害其活性，并与乳腺癌风险增加相关
DOI：
10.1038/onc.2014.443
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发表时间：
2015-10-01
期刊：
影响因子：
8
通讯作者：
Wang, Y.
中科院分区：
文献类型：
--
作者：
Wang, N.;Ding, H.;Wang, Y.
某些易感因素（例如 BRCA1/2 和 CHEK2 突变）会导致早期发生的家族性乳腺癌。在中国，乳腺癌的诊断年龄相对较年轻，40岁之前诊断的患者比例高于白人。然而，中国人群中 BRCA1/2 突变和报道的 CHEK2 种系突变的患病率要低得多或不存在，因此有必要研究中国乳腺癌患者中其他新的风险等位基因。在这项研究中，我们在中国年轻高危乳腺癌患者中搜索了 CHEK2 突变，并在 150 名患者中检测到了 12 名患者 (8.0%) 和 250 名健康对照中的 2 名患者 (0.8%，P= 0.0002) 中检测到了错义变异 Y390C (1169A> G)。其中四名 Y390C 携带者有乳腺癌和/或卵巢癌家族史。在没有家族史的患者中，Y390C 携带者往往会在 35 岁之前早期患乳腺癌。 Y390（位于 CHEK2 激酶结构域中的高度保守残基）的密码子变化似乎显着损害了 CHEK2 活性。功能分析表明，CHEK2 Y390C 突变是有害的，根据突变蛋白在 DNA 损伤后无法灭活 CDC25A 或激活 p53 的能力来判断。表达 CHEK2 Y390C 变体的细胞在 DNA 损伤后表现出 p21 和 Puma 表达受损，细胞周期检查点失调和凋亡反应可能有助于保存突变，从而促进肿瘤发生。综上所述，我们的结果不仅发现了一种与癌症家族相关并增加乳腺癌风险的新型 CHEK2 等位基因，而且还表明该等位基因在 DNA 损伤反应期间显着损害 CHEK2 功能。我们的研究结果进一步揭示了现有突变如何损害如此重要的癌症基因的功能，从而促进肿瘤发生。它还为乳腺癌监测、预防和管理提供了一个新课题。
Certain predisposition factors such as BRCA1/2 and CHEK2 mutations cause familial breast cancers that occur early. In China, breast cancers are diagnosed at relatively younger age, and higher percentage of patients are diagnosed before 40 years, than that in Caucasians. However, the prevalence for BRCA1/2 mutations and reported CHEK2 germline mutations is much lower or absent in Chinese population, arguing for the need to study other novel risk alleles among Chinese breast cancer patients. In this study, we searched for CHEK2 mutations in young, high-risk breast cancer patients in China and detected a missense variant Y390C (1169A> G) in 12 of 150 patients (8.0%) and 2 in 250 healthy controls (0.8%, P= 0.0002). Four of the Y390C carriers have family history of breast and/or ovarian cancer. In patients without family history, Y390C carriers tend to develop breast cancer early, before 35 years of age. The codon change at Y390, a highly conserved residue located in CHEK2’s kinase domain, appeared to significantly impair CHEK2 activity. Functional analysis suggested that the CHEK2 Y390C mutation is deleterious as judged by the mutant protein’s inability to inactivate CDC25A or to activate p53 after DNA damage. Cells expressing the CHEK2 Y390C variant showed impaired p21 and Puma expression after DNA damage, and the deregulated cell cycle checkpoint and apoptotic response may help conserve mutations and therefore contribute to tumorigeneisis. Taken together, our results not only identified a novel CHEK2 allele that is associated with cancer families and confers increased breast cancer risk, but also showed that this allele significantly impairs CHEK2 function during DNA damage response. Our results provide further insight on how the function of such an important cancer gene may be impaired by existing mutations to facilitate tumorigenesis. It also offers a new subject for breast cancer monitoring, prevention and management.