The Meningioma Consortium: Genome-Wide Association Study

脑膜瘤联盟：全基因组关联研究

• 批准号: 8089585
• 负责人: Elizabeth B. Claus
• 金额: $ 53.27万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8089585
• 关键词: ATM gene; ATM wt Allele; Accounting; Address; Adult; Age; Amendment; Area; Attention; BRCA1 gene; Benign; Biological; Brain Neoplasms; CCND1 gene; California; Cancer-Predisposing Gene; Case-Control Studies; Caucasians; Caucasoid Race; Cephalic; Clinical; Collection; Connecticut; County; DNA Repair Gene; Data; Data Collection; Diagnosis; Doctor of Philosophy; ERCC2 gene; Epidemiologic Studies; Ethnic Origin; Female; Funding; Genetic; Genetic Markers; Genotype; Geography; Hormones; Housing; Inherited; Interview; Ionizing radiation; KRAS2 gene; Link; Malignant Neoplasms; Massachusetts; Melissa; Neurologic; North Carolina; Pathologic; Patients; Phase; Predisposition; Prevention; Primary Brain Neoplasms; Process; Proteins; Quality of life; Radiation; Relative (related person); Request for Applications; Resources; Risk; Risk Factors; San Francisco; Series; Site; Specimen; Staging; Statutes and Laws; Study Subject; Targeted Research; Texas; Time; United States; United States National Institutes of Health; University Hospitals; Variant; Woman; ataxia telangiectasia mutated protein; benign brain tumor cancer registries; cancer genetics; case control; genetic analysis; genome wide association study; male; malignant breast neoplasm; meningioma; population based; public health relevance; sex; tumor

DESCRIPTION (provided by applicant): Meningioma is the most common primary brain tumor, present in up to one percent of adults, and although often considered benign, has survival comparable to breast cancer. Information on risk factors is extremely limited. In an effort to better define such factors, we are conducting a comprehensive population-based, case/control study of meningioma that includes 1600 cases and 1600 controls drawn from Massachusetts, Connecticut, North Carolina, California and Texas. This will represent the largest population-based collection of meningioma cases worldwide, with more than double the number of cases of any existing study. We are currently collecting biological specimens, and extensive exposure and phenotypic data with funding from the National Institutes of Health (NIH R01s CA109468, CA109461, CA109745, CA108473, and CA109475). In this application we request funds to genotype the study subjects to find inherited risk loci for meningioma. Our aims are to 1) Conduct the first genome wide association study (GWAS) of meningioma using the 1360 Caucasian cases from our ongoing case/control project and 3420 Caucasian controls drawn from the first half of three control series a) 600 controls from our ongoing case/control project, b) 1699 controls from Illumina iControlDB and c) 1121 controls from the Cancer Genetic Markers of Susceptibility (CGEMs) study, 2) Using 700 additional Caucasian meningioma subjects drawn from our clinical series and the second half of the above mentioned controls (n=3420), replicate candidates from Aim 1 that yielded p<10-5 for association with meningioma. Variants with p < 5.0*10-8 will be considered significant for genome wide association with meningioma risk from combined stage 1 and stage 2 analyses, 3) Replicate previous associations from the Interphone study8a of meningioma risk with variants in BRIP1 (the breast cancer susceptibility gene (BRCA1)-interacting protein) and ATM (ataxia telangiectasia mutated gene) and 4) Replicate previous associations from the Tineas Capitas study of meningioma risk with variants in DNA repair genes (KRAS2, ERCC2, CCND1).107 The proposed genetic analyses would represent the first GWAS data for meningioma and also provide important replication of previously observed associations with strong biological plausibility given the established association between meningioma risk and ionizing radiation. Identification of risk loci for meningioma will likely have strong etiologic significance with importance for both prevention and treatment. PUBLIC HEALTH RELEVANCE: Meningioma is the most common primary brain tumor, present in up to one percent of adults, and although often considered benign, has survival comparable to breast cancer. In this application we request funds to perform the first genome wide association study (GWAS) for meningioma using 2060 case subjects and 6833 control subjects and also provide important replication of previously observed associations with strong biological plausibility given the established association between meningioma risk and ionizing radiation. Identification of risk loci for meningioma will likely have strong etiologic significance with importance for both prevention and treatment.

描述(申请人提供)：脑膜瘤是最常见的原发脑瘤，存在于高达1%的成年人中，虽然通常被认为是良性的，但其存活率与乳腺癌相当。有关风险因素的信息极其有限。为了更好地定义这些因素，我们正在进行一项全面的基于人群的脑膜瘤病例/对照研究，包括来自马萨诸塞州、康涅狄格州、北卡罗来纳州、加利福尼亚州和德克萨斯州的1600例病例和1600名对照。这将是世界上最大的基于人群的脑膜瘤病例收集，病例数量是任何现有研究的两倍多。我们目前正在从美国国立卫生研究院(NIH R01s CA109468、CA109461、CA109745、CA108473和CA109475)收集生物标本以及广泛的暴露和表型数据。在这项申请中，我们申请资金对研究对象进行基因分型，以寻找脑膜瘤的遗传风险基因。我们的目标是：1)利用我们正在进行的病例/对照项目中的1360例高加索人病例和从我们正在进行的病例/对照项目的三个对照系列的前半部分中提取的3420名高加索人对照，对脑膜瘤进行第一次全基因组关联研究(GWAS)；a)从我们正在进行的病例/对照项目中提取600个对照；b)从Illumina iControlDB中提取1699个对照；以及c)从癌症遗传易感性标记(CGEM)研究中提取1121个对照，2)使用从我们的临床系列中另外700名高加索脑膜瘤受试者和上述对照中的后半部分(n=3420)，复制AIM 1中产生P&lt；10-5与脑膜瘤相关的候选病例。带有p&lt的变体；3)复制来自Interphone的脑膜瘤风险与BRIP1(乳腺癌易感基因(BRCA1)相互作用蛋白)和ATM(共济失调毛细血管扩张突变基因)变异之间的先前的关联，以及4)复制Tineas Capitas关于脑膜瘤风险与DNA修复基因(KRAS2、ERCC2、CCND1)变异的先前的关联。107拟议的遗传分析将是脑膜瘤的第一个GWAS数据，也提供了先前观察到的与强大的生物真实性的关联的重要复制，因为脑膜瘤风险和电离辐射之间已建立了关联。识别脑膜瘤的危险基因可能具有很强的病因学意义，对预防和治疗都很重要。 公共卫生相关性：脑膜瘤是最常见的原发脑瘤，存在于高达1%的成年人中，虽然通常被认为是良性的，但其存活率与乳腺癌相当。在这项申请中，我们申请资金，使用2060名病例受试者和6833名对照受试者对脑膜瘤进行第一次全基因组关联研究，并提供了先前观察到的具有很强生物学合理性的关联的重要复制，因为脑膜瘤风险和电离辐射之间的关联已建立。识别脑膜瘤的危险基因可能具有很强的病因学意义，对预防和治疗都很重要。