Interaction of Radiation, BRCA1/2, and Breast Cancer

放射、BRCA1/2 和乳腺癌的相互作用

• 批准号: 7125556
• 负责人: JONINE L. BERNSTEIN
• 金额: $ 82.85万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125556
• 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损伤的反应不足可导致癌症。然而，这些癌症的病因中可能涉及的基因-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这三个突变易导致乳腺癌的基因彼此之间存在复杂的相互作用，并且对dsb的正常细胞反应至关重要。因此，这些基因座上等位基因之间的相互作用可能对乳腺癌风险有重要影响，尤其是辐射诱发的乳腺癌。为了描述辐射暴露和遗传易感性在乳腺癌病因学中的作用，我们建议在2100名乳腺癌女性患者中确定BRCA1/2突变的患病率，这些女性患者已经获得了血液样本，并且已经确定了ATM突变状态。我们的研究假设是，携带突变BRCA1或BRCA2等位基因并接受RT作为原发性乳腺癌治疗的一部分的女性对侧乳腺癌的发病率会增加。这700个病例是患有双侧乳腺癌的女性分别与患有单侧乳腺癌的女性对照。我们的具体目标是：目标1。在以人群为基础的单侧和双侧乳腺癌年轻女性样本中检测生殖系BRCA1/2突变，采用DHPLC筛查和测序的分阶段方法。目标# 2。对BRCA1/2基因与环境的相互作用进行分析，重点是辐射暴露。为了实现这一目标，我们将收集医疗/治疗记录并重建对侧乳房的散射辐射剂量。一旦我们的研究完成，我们将为未来研究其他假定的乳腺癌基因和环境暴露，特别是辐射暴露，建立一个杰出的资源。

项目成果

Hierarchical modeling for estimating relative risks of rare genetic variants: properties of the pseudo-likelihood method.

• DOI: 10.1111/j.1541-0420.2010.01469.x
• 发表时间: 2011-06
• 期刊: Biometrics
• 影响因子: 1.9
• 作者: Capanu M;Begg CB
• 通讯作者: Begg CB

Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

• DOI: 10.1002/humu.21202
• 发表时间: 2010-03
• 期刊: HUMAN MUTATION
• 影响因子: 3.9
• 作者: Borg, Ake;Haile, Robert W.;Malone, Kathleen E.;Capanu, Marinela;Diep, Ahn;Torngren, Therese;Teraoka, Sharon;Begg, Colin B.;Thomas, Duncan C.;Concannon, Patrick;Mellemkjaer, Lene;Bernstein, Leslie;Tellhed, Lina;Xue, Shanyan;Olson, Eric R.;Liang, Xiaolin;Dolle, Jessica;Borresen-Dale, Anne-Lise;Bernstein, Jonine L.
• 通讯作者: Bernstein, Jonine L.