Environmental exposure: Susceptibility alleles in a DNA damage response pathway

描述(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停止，并修复或消除受损的细胞。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。这一途径中的几个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。这项研究的重点是先前有过辐射暴露的小鼠模型和人类队列。假设DNA损伤反应通路中的变异等位基因可能是良性的或产生适度的风险，但它们的不利影响在暴露后表现得更加深刻。一个小鼠模型模仿了一种易患乳腺癌的CHEK2变体。该等位基因纯合和杂合的小鼠将被评估其固有的DNA修复能力，以及它们是否更容易受到疾病和突变的影响，特别是暴露前后的有丝分裂重组和杂合性缺失。其他有Plk3、BRCA2和CDc25A缺陷或变异的小鼠模型已经制造出来或正在建造中。根据人体研究的结果，还将生产更多的模型。这两项人体研究将利用两个独特的队列，他们之前在环境中接触过辐射，后来患上了乳腺癌。对照人群由经历过类似接触但未患上疾病的个人组成。第一个队列由儿童时期接受过霍奇金病放射治疗并在多年后患上乳腺癌的患者组成。第二组患者在费尔纳德铀加工厂工作或居住在附近，并患上乳腺癌。具体地说，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的人群中过度表达。当这些等位基因被确定后，它们将被建模并在小鼠身上进行测试。最后，来自受影响个体的细胞将接受基因组不稳定性测试。简而言之，该项目评估了两个独特的暴露人群中一个途径内的等位基因变异，并对小鼠的基因类型进行了建模。由于这一途径对氧化应激诱导的损伤做出反应，而且这些等位基因可能对氧化应激敏感，因此将在携带不同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.