The Meningioma Consortium: Genome-Wide Association Study

描述（由申请人提供）：脑膜瘤是最常见的原发性脑肿瘤，存在于高达1%的成人中，尽管通常被认为是良性的，但其生存率与乳腺癌相当。关于风险因素的资料极为有限。为了更好地确定这些因素，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、加州和得克萨斯州的1600例病例和1600例对照。这将代表全球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。我们目前正在收集生物标本，以及由美国国立卫生研究院资助的广泛暴露和表型数据（NIH R 01 s CA 109468，CA 109461，CA 109745，CA 108473和CA 109475）。在这项申请中，我们要求资金对研究对象进行基因分型，以找到脑膜瘤的遗传风险位点。我们的目标是：1）使用来自我们正在进行的病例/对照项目的1360例白人病例和来自三个对照系列的前半部分的3420例白人对照进行脑膜瘤的第一次全基因组关联研究（GWAS）a）来自我们正在进行的病例/对照项目的600例对照，B）来自Illumina iControlDB的1699个对照和c）来自癌症易感性遗传标记（CGEM）研究的1121个对照，2）使用从我们的临床系列中抽取的另外700名高加索脑膜瘤受试者和上述对照的后一半（n=3420），与脑膜瘤相关性p<10-5的来自目标1的重复候选者。p < 5.0*10-8的变异体将被认为与脑膜瘤风险的全基因组关联是显著的，3）复制先前来自Interphone研究8a的脑膜瘤风险与BRIP变异的相关性1（乳腺癌易感基因（BRCA 1）相互作用蛋白）和ATM（共济失调毛细血管扩张突变基因）和4）复制先前来自Tineas Capitas研究的脑膜瘤风险与DNA修复基因变异的相关性（KRAS 2，ERCC 2，CCND1）.107拟议的遗传分析将代表脑膜瘤的第一个GWAS数据，并且还提供了先前观察到的具有强生物学可解释性的关联的重要复制，因为已经确定了以下之间的关联：脑膜瘤风险和电离辐射。确定脑膜瘤的危险位点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性脑肿瘤，存在于高达百分之一的成年人中，虽然通常被认为是良性的，但其生存率与乳腺癌相当。在本申请中，我们申请资金，使用2060例病例受试者和6833例对照受试者进行脑膜瘤的第一次全基因组关联研究（GWAS），并提供先前观察到的具有强生物学可验证性的关联的重要复制，因为脑膜瘤风险和电离辐射之间存在关联。确定脑膜瘤的危险位点可能具有很强的病因学意义，对预防和治疗都很重要。

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.