Breast Cancer Risk and Molecular Change After Chernobyl

描述（由申请人提供）：暴露于电离辐射是女性乳腺癌的一个原因，但对低剂量、长时间暴露于辐射对乳腺癌风险的影响知之甚少，对辐射相关乳腺癌的生物学机制也知之甚少。暴露于切尔诺贝利事故辐射的人口为调查这些问题提供了一个强大而独特的机会。本研究将利用这一机会，并有两个主要目的：1)调查绝经前乳腺癌的风险是否与切尔诺贝利事故对乳房的个人辐射剂量有关，估计每单位剂量的风险，调查剂量反应的形状，以及潜在的剂量效应修饰因素，包括分子特征和已确定的乳腺癌危险因素；2)探讨乳腺癌风险与辐射暴露的相关性是否因乳腺癌的特征而异，包括激素受体状态、基因组的损失和获得，以及14个选定的DMA修复基因的特异性改变。在2007年4月1日至2011年9月30日期间诊断出的在切尔诺贝利事故发生时居住在俄罗斯布良斯克州的绝经前乳腺癌病例将由一个独立的专家小组进行鉴定和诊断。对照将从布良斯克州无乳腺癌的女性居民中选择，并按出生日历年和1986年4月26日的居住地与病例相匹配。对于所有病例和对照组，将收集以下信息：1)人口统计和个人及家庭健康史；2)居住和饮食史，3)血液样本。将对每个病例和对照的个体乳房辐射剂量进行估计。每个病例将收集新鲜的乳腺肿瘤组织进行病理检查、免疫组织化学和纯肿瘤细胞样本的回收，并从这些细胞样本中提取DMA进行阵列研究、STR分析和甲基化分析。对于病例，将从组织和血液样本中提取和纯化DMA，以评估乳腺癌特征，包括激素受体状态、杂合性丧失、基因扩增和表观遗传基因失活，并估计这些特征与个体辐射剂量之间的关系。将从病例中收集妇科、产科和临床信息，以评估俄罗斯妇女乳腺癌已知危险因素的分布，包括生殖因素、乳腺癌和/或卵巢癌家族史、激素使用、饮酒、运动、体重指数和医疗辐照史，并调查它们对目标1和2中评估的剂量-反应关系的影响。

DESCRIPTION (provided by applicant): Exposure to ionizing radiation is well documented as a cause of breast cancer in women, but little is known about the effects on breast cancer risk of exposure to radiation at low doses, protracted over time, and the biologic mechanisms responsible for radiation associated breast cancer are poorly understood. Populations exposed to radiation from the Chernobyl accident provide a powerful and unique opportunity to investigate these questions. This study will capitalize on this opportunity and has two primary aims: 1) to investigate whether the risk of premenopausal breast cancer is associated with individual radiation dose to the breast from the Chernobyl accident, to estimate the risk per unit dose, to investigate the shape of the dose- response, and potential dose effect modifying factors, including molecular characteristics and established breast cancer risk factors; and 2) to investigate whether the association of breast cancer risk with radiation exposure differs according to characteristics of breast cancer, including hormone receptor status, genomic loss and gain, and specific alterations in 14 selected DMA repair genes. Premenopausal breast cancer cases diagnosed between 4/1/07 and 9/30/11 who were resident in the Bryansk Oblast of Russia at the time of the Chernobyl accident will be identified and their diagnosis confirmed by an independent panel of experts. Controls will be selected from female residents of the Bryansk Oblast without breast cancer and matched to cases by calendar year of birth and raion of residence on April 26, 1986. For all cases and controls the following will be collected: 1) demographic and personal and family health history; 2) residential and dietary history and 3) a blood sample. Individual radiation dose to the breast will be estimated for each case and control. Fresh breast tumor tissue will be collected for each case for pathology review, immunohistochemistry, and recovery of pure tumor cell samples, and DMA from these cell samples will be extracted for array studies, STR analysis and methylation assays. For cases DMA will be extracted and purified from tissue and blood samples to assess breast cancer characteristics, including hormone receptor status, loss of heterozygosity, gene amplification, and epigenetic gene inactivation, and to estimate the association between these characteristics and individual radiation dose. Gynecological, obstetrical, and clinical information will be collected from cases to assess the distribution of established risk factors for breast cancer in Russian women, including reproductive factors, family history of breast and/or ovarian cancer, hormone use, alcohol consumption, exercise, body mass index, and history of medical irradiation and to investigate their effect on the dose-response relationships assessed in Aims 1 and 2.