ATM mutations in breas cancer - a functional approach

电离辐射（IR）是一种已知的动物和人类乳腺癌致癌物。红外线照射会产生各种 DNA损伤，其中最危险的是DNA双链断裂（DSB）。基因组的不稳定性会导致 未修复的DSB的存在导致细胞死亡或恶性转化。真核生物已经进化 用于监测基因组完整性并通过细胞周期停滞，修复， 和/或凋亡机制。哺乳动物细胞DNA DSB反应途径的主要调节因子是 蛋白质ATM。ATM是乳腺癌相关基因编码的这一途径中的几种蛋白质之一 易感性尽管IR、乳腺癌和这些基因之间存在有趣的关系，但目前还没有明确的模型 这种特殊的生化途径如何对乳腺癌风险产生特定影响。我们现在已经开发了一个模型， ATM的作用。在这个“错义突变”模型中，我们提出ATM突变的一个子集通过显性突变起作用， 干扰，降低ATM的内在激酶活性，和/或破坏包括ATM的蛋白质复合物。的 模型预测ATM介导的乳腺癌风险是这类突变的携带者特有的，并建议 诸如IR的药剂是ATM的有效诱导剂，可能在这些个体中具有增强的致癌作用。 为了探索ATM、辐射暴露和乳腺癌之间的复杂关系，我们启动了 WECARE（妇女环境癌症和辐射暴露）研究，其中2100名妇女， 或非同步双侧乳腺癌。在这个集合中，乳腺癌的危险因素已经被评估， 调查问卷;全辐射剂量重建和ATM基因的全突变筛查都已完成。 贯彻对ATM数据的初步分析显示，第二次原发乳房的风险显著增加 接受放射治疗并携带ATM错义突变的受试者的癌症。然而，突变状态 测定仅基于对序列保守性的考虑无突变功能确认 在最初的研究中包括状态。在这个新的应用程序中，我们建议建立在这些初步研究结果的基础上 通过直接检验对侧乳腺癌的发病率在以下女性中增加的假设， 接受放射治疗作为治疗他们的第一个原发性乳腺癌和谁是特定ATM的携带者 等位基因，主要干扰细胞对IR的反应。我们的研究将表征假定的ATM 在WECARE筛选过程中鉴定的突变对DNA损伤反应的功能影响 途径，然后将这些信息纳入整个WECARE研究的变量分析中。

Ionizing radiation (IR) is a known breast carcinogen in both animals and humans. IR exposure generates a variety of lesions in DNA of which the most dangerous are DNA double strand breaks (DSBs). Genomic instability can result from the presence of unrepaired DSBs leading to cell death or malignant transformation. Eukaryotes have evolved efficient systems for monitoring genomic integrity and responding rapidly to their presence via cell cycle arrest, repair, and/or apoptotic mechanisms. The master regulator of the mammalian cellular DNA DSB response pathway is the protein ATM. ATM is one of several proteins in this pathway encoded by genes implicated in breast cancer susceptibility. Despite the intriguing relationship between IR, breast cancer, and these genes, there is no clear model for how this particular biochemical pathway has specific effects on breast cancer risk. We have now developed a model for the role of ATM. In this "missense-mutation" model we propose that a subset of ATM mutations act by dominant interference, reducing the intrinsic kinase activity of ATM, and/or disruptingprotein complexes that includeATM. The model predicts that ATM-mediated risk for breast cancer is specific to carriers of this class of mutation and suggests that agents such as IR, which are potent inducers of ATM, may have enhanced carcinogenic effects in such individuals. In order to explore the complex relationship between ATM, radiation exposure and breast cancer, we initiated the WECARE (Women's Environment Cancer And Radiation Exposure) study in which 2100 women with either unilateral or asynchronous bilateral breast cancer are enrolled. In this collection, breast cancer risk factors have been assessed by questionnaire; both full radiation dosimetry reconstruction, and full mutation screening of the ATMgene have been carried out. Preliminary analysis of the ATM data reveals a significant increase in risk for second primary breast cancers in subjects who received radiation therapy and carry ATM missense mutations. However, mutation status determination was based only on consideration of sequence conservationno functional confirmation ofmutation status was included in the original study. In this new application, we propose to build upon these preliminary findings by directly testing the hypothesis that the incidence of contralateral breast cancer is increased among women who received radiation therapy as a treatment for their first primary breast cancer and who are carriers of specific ATM alleles which dominantly interfere with the cellular response to IR. Our studies will characterize putative ATM mutations identified in the course of WECARE screening for their functional effects on DNA damage response pathways, and then incorporate this information into the analysis of variables for the overall WECARE study.