DNA REPAIR GENOTYPE AND PHENOTYPE IN BREAST CANCER RISK

描述(由申请人提供)： 这是一项将DNA修复中的多态与乳腺癌发病率联系起来的努力。 癌症。BER和HRR通路中的突变被认为是使 个体对电离辐射和乳腺癌更敏感。化验 还将评估这些途径中活动减少的情况。我们的 癌症预防的长期目标是通过以下方式识别高危人群 利用DNA修复标记设计基于机制的预防策略 根据个人的具体风险情况量身定做。人类细胞是 持续接触外源性和内源性致癌物，能够引起 DNA损伤。有效的修复对于保持基因组的完整性和 DNA修复过程中的遗传变异可能会影响个体对 癌症。我们的工作假设是DNA修复基因的多态与 非保守氨基酸替代可能导致蛋白质功能改变 在DNA修复和乳腺癌风险增加方面。各种人造的治疗方法， 诊断或职业性电离辐射暴露与 人类患乳腺癌的风险。IR引起的DNA损伤的种类主要有 碱基切除修复(BER)和同源重组修复 (HRR)。我们初步研究的数据支持这样一个假设，即基因的多态 BER和HRR基因可能与电离超敏有关 辐射和乳腺癌的易感性。为了实现我们的长期目标， 这项研究的主要目标是确定DNA修复基因和 表型在乳腺癌风险评估中的应用。次要目标是 开发更具体的BER和HRR活动分析，以评估 个体DNA修复基因变异在应答中的功能意义 致IR。这项研究将使用现有的基因组DNA，冷冻保存的淋巴细胞， 和问卷数据收集在正在进行的NCI资助(CA73629)乳房 癌症病例对照研究。研究对象将包括200名新的 确诊、未经治疗的乳腺癌病例和200名对照(频率匹配 到从Wake招募的种族和年龄[等于或小于5岁]的案例 森林大学浸信会医学中心。一份问卷被用来收集 关于已确定的乳腺癌风险因素的信息。这项拟议的研究 特别具有成本效益和效率，因为最昂贵的任务 (例如，招聘和收集样本和数据)由 家长研究。存活的淋巴细胞将提供一个极其独特的机会 研究DNA修复变异体的功能意义，这是 对评估DNA修复基因SNPs的有用性至关重要 易感标志物。

DESCRIPTION (provided by applicant): This is an effort to relate polymorphisms in DNA repair to incidence of breast cancer. Mutations in both the BER and HRR pathways are proposed to make an individual more sensitive to ionizing radiation and breast cancer. Assays for assessing decreased activity in these pathways will also be pursued. Our long-term goal in cancer prevention is to identify high-risk populations by using DNA repair markers and to design mechanistic-based prevention strategy tailored to the specific risk profiles of individuals. Human cells are constantly exposed to exogenous and endogenous carcinogens capable of causing DNA damage. Efficient repair is critical in maintaining genome integrity and genetic variability in DNA repair may influence individual's susceptibility to cancer. Our working hypothesis is that polymorphism of DNA repair genes with nonconservative amino acid substitution may lead to altered protein function in DNA repair and elevated breast cancer risk. Various man-made therapeutic, diagnostic, or occupational exposure to ionizing radiation have been linked to human breast cancer risk. The variety of DNA lesions induced by IR are mainly repaired by base excision repair (BER) and homologous recombinational repair (HRR). Data from our pilot study support the hypothesis that polymorphisms of genes in BER and HRR may be associated with hypersensitivity to ionizing radiation and susceptibility to breast cancer. To achieve our long-term goal, the primary objective of this study is to characterize DNA repair genotype and phenotype in breast cancer risk assessment. The secondary objective is to develop more specific activity assays for BER and HRR in order to evaluate the functional significance of individual DNA repair genetic variant in response to IR. This study will use existing genomic DNA, cryopreserved lymphocytes, and questionnaire data collected in an ongoing NCI-funded (CA73629) breast cancer case-control study. The study subjects will include 200 newly diagnosed, untreated breast cancer cases and 200 controls (frequency-matched to cases on race and age [equal to or less than 5 yrs]) recruited from Wake Forest University Baptist Medical Center. A questionnaire was use to collect information on established breast cancer risk factors. This proposed research is exceptionally cost-effective and efficient since the most costly tasks (e.g., recruitment and collection of samples and data) are supported by the parent study. Viable lymphocytes will provide an extremely unique opportunity to investigate the functional significance of DNA repair variants, which is crucial in evaluating the usefulness of SNPs of DNA repair genes as susceptibility markers.