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

Barrett 和食管腺癌遗传易感性研究 (BEAGESS)

• 批准号: 7730733
• 负责人: THOMAS L VAUGHAN
• 金额: $ 344.89万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7730733
• 关键词: Apoptosis; Barrett Esophagus; Biological; Blood specimen; Cancer Etiology; Candidate Disease Gene; Chronic; Complex; DNA; DNA Damage; DNA Repair; Data; Development; Disease; Environmental Risk Factor; Epidemic; Epidemiologic Studies; Epithelium; Esophageal; Esophageal Adenocarcinoma; Etiology; Family; Female; Funding; Gastroesophageal reflux disease; Gender; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome; Genomics; Genotype; Goals; Gonadal Steroid Hormones; Human; Incidence; Individual; Inflammation; Inflammatory; Insulin Resistance; Interview; Knowledge; Light; Malignant Neoplasms; Mediating; Meta-Analysis; Metabolic; Methods; Modeling; Neoplastic Processes; Obesity; Overweight; Oxidative Stress; Participant; Pathogenesis; Pathway interactions; Pattern; Persons; Phase; Play; Population Control; Precancerous Conditions; Predisposition; Prevalence; Prevention; Process; Reflux; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Sampling; Screening procedure; Severities; Source; Stimulation of Cell Proliferation; Symptoms; Syndrome; Technology; Telomere Maintenance; Telomere Shortening; Twin Multiple Birth; Variant; abdominal pressure; cancer risk; cigarette smoking; cofactor; cost; design; genetic risk factor; genome wide association study; high risk; male; model development; modifiable risk; population based; public health relevance

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.

描述（由申请人提供）：食管腺癌 (EA) 是一种快速致命的疾病，在过去三十年中，其发病率在美国的增长速度超过任何其他癌症 - 超过 500%。胃食管反流和肥胖已被发现是 EA 及其主要前体巴雷特食管 (BE) 发生的关键可改变危险因素。然而，虽然反流似乎对肿瘤形成过程至关重要，但只有约 10-15% 患有长期反流症状的人在其一生中会患上 BE；在那些这样做的人中，大多数都没有进展到 EA。同样，肥胖增加 EA 风险的机制尚不清楚。因此，必须有其他辅助因子来调节与反流相关的对食管上皮的慢性炎症作用以及超重的局部和全身后果，这在很大程度上决定了风险。其中许多辅助因子可能是遗传介导的，虽然家庭、双胞胎和候选基因研究支持这一观点，但尚未确定任何基因发挥因果作用。在这里，我们提出了一项大规模全基因组关联研究，该研究利用了巴雷特氏病和食管腺癌联盟 (BEACON) 的研究人员在 18 项流行病学研究中收集的广泛数据，这些数据代表了世界上针对这些疾病精心设计的、以人群为基础的研究中的绝大多数。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。主要目的是识别与 BE 和 EA 风险最密切相关的 tagSNP。在次要目标中，我们将评估最显着的关联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）而变化的程度。我们提出了三年内的单阶段方法，涉及 7,500 名参与者，所有参与者之前都接受过有关主要环境和宿主风险因素的采访，并捐赠了血液样本。 Illumina Infinium Human 610-Quad 芯片将用于对大约 1,500 个 EA 病例、3,000 个 BE 病例和 3,000 个群体对照进行基因分型。已经确定了其他样本和数据来源，以提供复制研究（资金需单独申请）。BEACON 的资源以及基因组技术和分析方法的最新进展，提供了一个独特且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) 帮助识别其发病机制中的关键生物途径，以及 c) 帮助针对最高风险人群，以便 可以最有效地指导筛查、预防和监测工作。公共卫生相关性：食管腺癌是一种快速致命的疾病，其发病率在过去 30 年中增加了六倍多。通过使用 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这种癌症及其主要癌前病变巴雷特食管风险的影响，并根据这些疾病的关键环境和宿主风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这种癌症病因学中重要的生物学途径，并帮助针对风险最高的人群，以便最有效地指导筛查、预防和监测工作。