Interaction of Radiation, BRCA1/2, and Breast Cancer

放射、BRCA1/2 和乳腺癌的相互作用

• 批准号: 6663118
• 负责人: JONINE L. BERNSTEIN
• 金额: $ 90.52万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-24 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6663118
• 关键词: DNA damage; adult human (21+); brca gene; breast neoplasms; cancer risk; clinical research; disease /disorder etiology; female; gene environment interaction; gene mutation; genetic susceptibility; high performance liquid chromatography; human subject; neoplasm /cancer genetics; neoplasm /cancer radiation therapy; nucleic acid sequence; patient oriented research; radiation dosage; radiation related neoplasm /cancer; therapy adverse effect; women's health

DESCRIPTION (provided by applicant): Deficiencies in cellular response to DNA damage can predispose to cancer. However, the gene-environment interactions that may be involved in the etiology of these cancers are poorly understood. One important environmental cause of DNA damage is exposure to ionizing radiation leading to the formation of DNA double-strand breaks (DSB). Recent evidence demonstrates that three genes in which mutations predispose to breast cancer, BRCA1/2 and ATM have complex interactions with each other and are essential for the normal cellular response to DSBs. Therefore, interaction between alleles at these loci may have important effects on breast cancer risk, in general, and radiation-induced breast cancer, in particular. To delineate the roles of radiation exposure and genetic predisposition in the etiology of breast cancer, we propose to determine the prevalence of BRCA1/2 mutations in a well characterized population-based sample of 2100 women with breast cancer for whom blood samples have already been obtained and ATM mutation status already determined. Our study hypothesis is that the incidence of contralateral breast cancer will be increased among women who are carriers of mutant BRCA1 or BRCA2 alleles and who received RT as part of treatment for first primary breast cancer. The 700 cases are women with bilateral breast cancer individually countermatched to two controls, women with unilateral breast cancer. Our specific aims are: Aim #1. To test for germline BRCA1/2 mutations in a population-based sample of young women with unilateral and bilateral breast cancer, using a staged approach with DHPLC screening followed by sequencing. Aim #2. To conduct analyses of gene-environment interactions for BRCA1/2 with a focus on radiation exposure. To achieve this aim, we will collect medical/treatment records and recreate the scatter radiation dose to the contralateral breast. Once our study has been completed, we will have established an outstanding resource for future studies of other putative breast cancer genes and environmental exposures, with a particular focus on radiation exposure.

描述(由申请人提供)：细胞对DNA损伤的反应不足可能易患癌症。然而，可能与这些癌症的病因学有关的基因-环境相互作用却知之甚少。DNA损伤的一个重要环境原因是暴露于电离辐射，导致DNA双链断裂(DSB)的形成。最近的证据表明，BRCA1/2和ATM三个突变易患乳腺癌的基因之间存在复杂的相互作用，对于正常的细胞对DSB的反应是必不可少的。因此，这些基因座的等位基因之间的相互作用可能对乳腺癌的总体风险，特别是辐射诱发的乳腺癌风险有重要的影响。为了阐明辐射暴露和遗传易感性在乳腺癌病因学中的作用，我们建议确定BRCA1/2突变在2100名乳腺癌女性患者中的流行率，这些患者的血液样本已经得到采集，ATM突变状态已经确定。我们的研究假设是，BRCA1或BRCA2突变等位基因携带者和接受放射治疗作为第一原发乳腺癌治疗一部分的女性，对侧乳腺癌的发病率将增加。这700例患者是患有双侧乳腺癌的女性，与两名患有单侧乳腺癌的女性对照。我们的具体目标是：目标#1.采用分阶段的方法检测单侧和双侧乳腺癌年轻女性样本中的胚系BRCA1/2突变，采用DHPLC筛查和测序相结合的方法。目的#2.分析BRCA1/2的基因-环境相互作用，重点放在辐射暴露上。为了达到这一目的，我们将收集医疗/治疗记录，并重新计算对侧乳房的散射辐射剂量。一旦我们的研究完成，我们将为未来其他可能的乳腺癌基因和环境暴露的研究建立一个杰出的资源，特别是辐射暴露。