BREAST CANCER, RADIATION EXPOSURE, AND THE ATM GENE

本研究的目的是探讨基因-环境相互作用在乳腺癌的病因。 我们建议建立一个流行病学危险因素信息和生物标本的知识库，这些信息和生物标本来自900名患有非同步双侧乳腺癌的女性和2700名患有单侧乳腺癌的女性，这些女性将通过美国和丹麦的6个基于人群的肿瘤登记处来确定。 将使用结构化问卷对所有受试者进行访谈，并采集血液样本进行遗传分析。 我们使用这个储存库的最初计划是检查辐射暴露，ATM基因和乳腺癌的相互作用。 已知电离辐射是乳腺癌的致癌物，最近的研究表明ATM基因可能增加对辐射诱发的乳腺癌的易感性。 我们的假设是，ATM基因携带者和接受过放射治疗作为乳房保护治疗的一部分的妇女，发生第二原发性对侧乳腺癌的风险特别高。 我们还将提供关于ATM在这一大规模基于人群的女性样本中的患病率的描述性统计数据。 ATM杂合性将通过适用于分析该复杂基因的有效分阶段方法进行评估。 对于接受RT的受试者，将重建对侧乳房的辐射散射剂量。我们建立的独特的知识库将是关键的跨学科研究的机制和性质的基因-基因和基因-环境相互作用影响乳腺癌的易感性。 对第二原发性乳腺癌的研究提供了一个特别有希望的背景，可以解开影响乳腺癌发生的激素，遗传和环境因素之间的复杂相互作用，因为任何重要的病因因素（例如遗传异常）在已经患有乳腺癌的女性中比在一般人群中更普遍。 此外，乳腺癌发病率的上升加上生存率的提高，使越来越多的妇女面临第二原发性乳腺癌的风险，使其成为一个具有公共卫生重要性的问题。

The objective of this study is to investigate gene-environment interactions in the etiology of breast cancer. We propose to establish a repository of epidemiologic risk factor information and biologic specimens from 900 women with asynchronous bilateral breast cancer and 2700 women with unilateral breast cancer who will be ascertained through 6 population-based tumor registries in the US and Denmark. All subjects will be interviewed using a structured questionnaire and blood samples will be collected for genetic analyses. Our initial plan for using this repository is to examine the interaction of radiation exposure, the ATM gene, and breast cancer. Ionizing radiation is known to be a breast carcinogen and recent studies suggest that the ATM gene may increase susceptibility to radiation-induced breast cancer. Our hypothesis is that women who are ATM gene carriers and who have received radiation therapy as part of breast conservation treatment, are at especially high risk of developing second primary contralateral breast cancer. We will also provide descriptive statistics on the prevalence of ATM in this large population-based sample of women. ATM heterozygosity will be assessed through an efficient staged approach appropriate for analysis of this complex gene. For subjects who received RT, radiation scatter dose to the contralateral breast will be reconstructed. The unique repository that we establish will be critical for future interdisciplinary investigations into the mechanisms and nature of gene-gene and gene-environment interaction influencing susceptibility to breast cancer. The study of second primaries presents a particularly promising context in which to disentangle the complex interactions among hormonal, genetic, and environmental factors influencing breast carcinogenesis as any important etiologic factors (e.g. genetic abnormalities) will be more prevalent among women who already have breast cancer than in the general population. Further, the rising incidence of breast cancer coupled with improved survival, has placed an increased number of women at risk for second primary breast cancer making it an issue of public health importance.