Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study (BEAGESS)

描述（由申请人提供）：食管腺癌（EA）是一种快速致命的疾病，在过去的三十年中，其发病率的增长速度超过了美国任何其他癌症-超过500%。胃食管反流和肥胖已被发现是EA及其主要前体Barrett食管（be）发展的关键可改变危险因素。然而，虽然反流似乎对肿瘤过程至关重要，但只有约10 - 15%的长期反流症状的个体在其一生中发展为be；在这些人中，大多数不会发展为EA。同样，肥胖增加EA风险的机制尚不清楚。因此，必须有其他辅助因素调节反流相关的慢性炎症对食管上皮的影响以及超重的局部和全身后果，这些因素在很大程度上决定了风险。许多这些辅助因素很可能是遗传介导的，虽然家庭、双胞胎和候选基因研究支持这一观点，但还没有基因被确定为起因果作用。在这里，我们提出了一项大规模的全基因组关联研究，该研究利用了巴雷特和食管腺癌协会（BEACON）在18项流行病学研究中收集的大量数据，代表了世界上绝大多数设计良好的基于人群的这些疾病研究。我们研究的总体目标是评估遗传易感性对EA和BE风险的影响。主要目的是确定与BE和EA风险最密切相关的标签snp。次要目的是根据这些疾病的关键环境和宿主风险因素，包括性别、肥胖和吸烟，评估最显著的关联变化程度。我们提出了一个为期三年的单阶段方法，涉及7500名参与者，所有参与者之前都接受过关于主要环境和宿主风险因素的访谈，并捐献了血液样本。Illumina Infinium Human 610-Quad芯片将用于约1500例EA、3000例be和3000例人群对照的基因分型。已经确定了其他样本和数据来源，以提供重复性研究（资金将另行申请）。BEACON的资源，加上基因组技术和分析方法的最新进展，提供了一个独特和具有成本效益的机会：a)研究遗传和环境因素对这些重要疾病病因的影响，b)帮助确定其发病机制中的关键生物学途径，以及c)帮助确定高危人群，以便最有效地指导筛查、预防和监测工作。公共卫生相关性：食管癌是一种迅速致命的疾病，其发病率在过去30年中增加了6倍以上。通过对18项流行病学研究的汇总数据和DNA进行大规模全基因组关联研究，我们建议评估遗传易感性对该癌症及其主要癌前病变Barrett食管风险的影响，并根据这些疾病的关键环境和宿主危险因素确定易感性因素的变化程度。这些结果将有助于确定在这种癌症的病因学中重要的生物学途径，并帮助确定高危人群，以便最有效地指导筛查、预防和监测工作。

DESCRIPTION (provided by applicant): The incidence of esophageal adenocarcinoma (EA), a rapidly fatal disease, has increased faster than any other cancer in the US over the last three decades - over 500 percent. Gastroesophageal reflux and obesity have been found to be key modifiable risk factors for the development of EA and its main precursor, Barrett's esophagus (BE). However, while reflux appears to be crucial to the neoplastic process, only about 10 - 15 percent of individuals with long-standing reflux symptoms develop BE in their lifetimes; among those who do, most do not progress to EA. Similarly, the mechanisms by which obesity increases risk of EA are not known. Thus, there must be other cofactors modulating the reflux-related chronic inflammatory effects on the esophageal epithelium and the local and systemic consequences of being overweight, that largely determine risk. Many of these cofactors are likely to be genetically mediated, and while family, twin and candidate gene studies support this notion, no genes have been established yet as playing a causal role. Here, we propose a large-scale genome-wide association study which takes advantage of the extensive data collected by investigators in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) in 18 epidemiologic studies, representing the vast majority of the well-designed largely population-based studies of these diseases in the world. The overall goal of our research is to evaluate the influence of genetic susceptibility on risk of EA and BE. The primary aim is to identify tagSNPs most strongly associated with risk of BE and EA. In secondary aims we will evaluate the extent to which the most significant associations vary according to key environmental and host risk factors for these conditions, including gender, obesity and cigarette smoking. We propose a single phase approach over three years involving 7,500 participants, all of whom have been previously interviewed regarding major environmental and host risk factors and have donated blood specimens. The Illumina Infinium Human 610-Quad Chip will be used to genotype approximately 1,500 cases of EA, 3,000 cases of BE and 3,000 population controls. Additional sources of samples and data have been identified to provide replication studies (funding to be requested separately.) The resources of BEACON, together with recent advances in genomic technology and analytic methods, present a unique and cost-effective opportunity to a) study the influence of genetic and environmental factors in the etiology of these important diseases, b) aid in the identification of key biological pathways in their pathogenesis, and c) help target persons at highest risk so that screening, prevention and surveillance efforts can be directed most effectively. PUBLIC HEALTH RELEVANCE: The incidence of esophageal adenocarcinoma, a rapidly fatal disease, has increased more than six-fold over the past 30 years. By conducting a large-scale genome-wide association study using pooled data and DNA from 18 epidemiologic studies, we propose to evaluate the influence of genetic susceptibility on risk of this cancer and its main precancerous condition, Barrett's esophagus, and determine the extent to which susceptibility factors vary according to key environmental and host risk factors for these conditions. These results will aid in the identification of biological pathways important in the etiology of this cancer, and help target persons at highest risk so that screening, prevention and surveillance efforts can be directed most effectively.