The Meningioma Consortium: Genome-Wide Association Study

项目摘要/摘要 脑膜瘤是最常见的原发脑瘤，出现在高达1%的成年人中，并且 虽然通常被认为是良性的，但其存活率与乳腺癌相当。关于风险的信息 这些因素极其有限。为了更好地界定这些因素，我们正在进行一项 脑膜瘤的综合人群病例/对照研究，包括1600例和 1600个控制来自马萨诸塞州、康涅狄格州、北卡罗来纳州、加利福尼亚州和德克萨斯州。这 将是世界上最大的以人群为基础的脑膜瘤病例集合，超过 将任何现有研究的病例数量增加一倍。我们目前正在收集生物标本， 和广泛的暴露和表型数据，由美国国立卫生研究院(NIH)资助 R01S CA109468、CA109461、CA109745、CA108473和CA109475)。在本申请中，我们请求 资金用于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) 首次使用1360名高加索人进行脑膜瘤全基因组关联研究 我们正在进行的病例/控制项目的病例和#年上半年的3420名高加索人对照病例 三个控制系列a)600个控制来自我们正在进行的病例/控制项目，b)1699个控制来自 Illumina iControlDB和c)1121来自癌症遗传易感性标记(CGEM)的对照 研究，2)使用700名额外的高加索脑膜瘤受试者从我们的临床系列和 上述对照的后半部分(n=3420)，复制来自目标1的候选，产生 与脑膜瘤有关的P&lt；10-5。P&lt；5.0*10-8的变体将被认为是重要的 来自1期和2期联合分析的全基因组与脑膜瘤风险的相关性，3) 复制来自Interphone研究8a的脑膜瘤风险与BRIP1变异之间的先前关联 (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症 基因突变)和4)复制了Tineas Capitas对脑膜瘤的研究中以前的关联 DNA修复基因变异(KRAS2、ERCC2、CCND1)的风险。107拟议的遗传分析 将代表第一个脑膜瘤的GWAS数据，并提供重要的复制 先前观察到的关联具有很强的生物学可信度，因为已建立的关联 脑膜瘤风险和电离辐射之间的关系。脑膜瘤危险基因的识别将很有可能 具有很强的病因学意义，对预防和治疗具有重要意义。

Project Summary/ Abstract 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.