Environmental exposure: Susceptibility alleles in a DNA damage response pathway

描述（由申请人提供）：当DNA受损时，细胞启动信号级联，导致细胞周期检查点阻滞和损伤修复或受损细胞的消除。双链DNA断裂后激活的一条途径涉及ATM和其他DNA损伤反应蛋白，包括CHEK2、Cdc25A、Plk3、BRCA1和BRCA2。在这一途径中，一些有助于基因组稳定性的基因具有易患疾病的变异等位基因。这项研究的重点是小鼠模型和先前有辐射暴露的人类队列。假设DNA损伤反应途径中的变异等位基因可能是良性的或产生适度的风险，但它们的不良影响在暴露后表现得更加深刻。一种小鼠模型模拟了易患乳腺癌的CHEK2变异。该等位基因的纯合和杂合小鼠将被评估其固有的DNA修复能力，以及它们是否更容易患病和突变，特别是暴露前后的有丝分裂重组和LOH。其他Plk3、BRCA2和Cdc25A缺乏或变异的小鼠模型已经制作或正在构建中。根据人类研究的结果，将产生更多的模型。人体研究将利用两组独特的人群，他们之前以辐射的形式暴露在环境中，后来患上了乳腺癌。对照人群由经历过类似暴露但未发病的个体组成。第一组研究对象是儿童时期因霍奇金病接受放射治疗，几年后发展为乳腺癌的患者。第二组研究对象是在弗纳尔德铀加工厂工作或居住在其附近并患有乳腺癌的患者。具体来说，我们将询问DNA损伤反应途径中的变异等位基因是否单独或组合在受影响人群中过度代表。当这些等位基因被识别出来后，它们将在老鼠身上进行建模和测试。最后，将对来自受影响个体的细胞进行基因组不稳定性测试。简而言之，该项目在两个独特的暴露人群中评估了一条通路内的等位基因变异，并对小鼠的基因型进行了建模。由于这一途径对氧化应激引起的损伤作出反应，并且由于这些等位基因可能对氧化应激敏感，因此将在携带变异等位基因的小鼠模型中测试抗氧化剂预防疾病的能力。

DESCRIPTION (provided by applicant): When DNA is damaged, cells initiate a signaling cascade that results in cell cycle checkpoint arrest and repair of the damage or elimination of the damaged cells. One pathway that is activated following a double strand DNA break involves ATM and other DNA damage response proteins including CHEK2, Cdc25A, Plk3, BRCA1 and BRCA2. Several genes in this pathway, which contribute to genomic stability, have variant alleles that predispose to disease. This study focuses on mouse models and human cohorts who have had prior radiation exposure. The hypothesis is that variant alleles within the DNA damage response pathway may be benign or produce a modest risk, but that their adverse effects manifest more profoundly after exposure. One mouse model mimicks a CHEK2 variant that predisposes to breast cancer. Mice homozygous and heterozygous for this allele will be assessed for their inherent DNA repair capacity and whether they are more susceptible to disease and to mutagenesis, particularly to mitotic recombination and LOH before and after exposure. Other mouse models with deficiencies or variants in Plk3, BRCA2, and Cdc25A, have been made or are under construction. Additional models, dictated by the outcome of the human studies, will be produced. The human studies will utilize two unique cohorts with prior environmental exposure in the form of radiation who subsequently developed breast cancer. A control population consists of individuals who have experienced similar exposure but have not developed disease. The first cohort consists of patients who as children were treated with radiation for Hodgkin disease and years later developed breast cancer. The second cohort involves patients who worked at or lived in close proximity to the Fernald Uranium processing plant and have developed breast cancer. Specifically, we will ask whether variant alleles within the DNA damage response pathway, singly or in combination, are overrepresented in the affected population. When such alleles are identified, they will be modeled and tested in the mouse. Lastly, cells from affected individuals will be tested for genomic instability. In brief, this project assesses allelic variants within a pathway in two unique exposed populations and models the genotypes in mice. Since this pathway responds to damage induced by oxidative stress and since these alleles may sensitize to oxidative stress, the capacity of antioxidants to prevent disease in mouse models carrying variant alleles will be tested.