BREAST CANCER, RADIATION EXPOSURE, AND THE ATM GENE

本研究的目的是探讨乳腺癌病因学中的基因-环境交互作用。我们建议建立一个流行病学危险因素信息库和生物标本库，其中包括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，这些患者将通过美国和丹麦的6个基于人群的肿瘤登记得到确认。所有受试者将使用结构化问卷进行访谈，并将采集血液样本进行基因分析。我们使用这个资料库的最初计划是检查辐射暴露、ATM基因和乳腺癌之间的相互作用。众所周知，电离辐射是一种乳腺癌致癌物质，最近的研究表明，ATM基因可能会增加辐射诱发乳腺癌的易感性。我们的假设是，ATM基因携带者和接受过放射治疗作为保乳治疗一部分的女性，患第二原发对侧乳腺癌的风险特别高。我们还将提供关于在这个以人口为基础的大样本妇女中ATM流行率的描述性统计数据。ATM杂合性将通过一种适合于分析这一复杂基因的有效阶段性方法进行评估。对于接受放射治疗的受试者，将重建对侧乳房的辐射散射剂量。我们建立的独特的信息库将对未来跨学科研究影响乳腺癌易感性的基因-基因和基因-环境相互作用的机制和性质至关重要。对第二原发癌的研究提供了一个特别有希望的背景，可以在其中理清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妇女中将比普通人群中更普遍。此外，乳腺癌发病率的上升，加上存活率的提高，使越来越多的妇女面临患第二原发乳腺癌的风险，使其成为公共卫生的重要问题。

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.