Genetic and Molecular Epidemiology of Adult Glioma

描述(由申请人提供)：恶性胶质瘤通常是一种衰弱的、迅速致命的癌症。很少有影响胶质瘤病因或预后的一致因素出现，可能是由于组织类型内和组织类型之间的病因和进展途径的异质性。许多研究表明遗传易感性以及环境和免疫因素在胶质瘤形成中起作用。除了年龄、放射治疗和切除等既定因素外，遗传变异和肿瘤标志物也可能影响患者的生存。这项建议建立在15年研究的基础上，以增加对这些和其他与成人胶质瘤病因和预后相关的因素的了解，这些因素和对照具有良好的特征性。在这两个阶段的研究中，我们将对900例现有星形细胞病患者和700名对照的构成DNA进行大约10,000个单核苷酸多态(SNPs)的基因分型，并在新的受试者组中确认重要的SNPs。我们将(1)使用功能基因组和生物信息学工具(如GenMAPP、SIFT、HapMap)查询和集成基因组和功能数据库，以基于明确定义的优先标准(已验证的、非同义编码或其他等位基因频率为5%的功能SNP优先用于可能与胶质瘤发病相关的候选染色体区域、基因和途径，其余跨越整个基因组)；(2)使用来自10,000个SNPs的基因分型结果，识别400-1500个可能与病例控制状态(Logistic回归)、病例生存(Cox回归)和病例诊断年龄(方差分析)相关的SNPs，使用置换测试来识别错误发现率较低的SNPs的子集，并使用诸如随机森林、逻辑回归和基因组学工具等其他建模方法来定义相互作用的SNPs并增强真实发现；(3)(A)从5/06-12/09和500个基于人群的对照中诊断出另外950例胶质瘤(约500例基于人群和450例基于临床)，获得血液、口腔和肿瘤样本，以及关于家族和个人病史、职业和饮食偏好的治疗和问卷数据，(B)根据神经病理学检查和肿瘤标记物(P53和EGFR的基因和表达变化)对肿瘤进行分类，(C)进行IgE和病毒学IgG血清学研究，以及(D)为先前发现的SNP(以及其他可能与它们处于强烈连锁失衡的SNP)对新的星形细胞病例和对照进行基因分型；以及(4)适当整合SNP、人口统计学、环境、免疫学、治疗和肿瘤数据，以确定与胶质瘤病因和预后相关的因素。公共卫生意义：每年约有1.3万美国人死于原发脑癌；在所有癌症部位中，它们位居首位，平均寿命损失数年；30多年来，在提高胶质母细胞瘤存活率方面进展甚微；这项研究将有助于识别导致这些癌症的因素，并可能预测存活率。加强对这些因素的了解可能会为未来的干预措施提供目标。

DESCRIPTION (provided by applicant): Malignant gliomas are often debilitating, rapidly fatal cancers. Few consistent factors influencing glioma etiology or prognosis have emerged, likely due to heterogeneity of causal and progression pathways within and between histologic types. Many studies suggest a role for inherited susceptibility and environmental and immunologic factors in gliomagenesis. Inherited variation and tumor markers may also influence survival, in addition to established factors such as age, radiation therapy, and resection. This proposal builds on 15 years of studies to increase understanding of these and other factors associated with adult glioma etiology and prognosis among well-characterized cases and controls. In this two phase study, we will genotype constitutive DNA from 900 existing astrocytic cases and 700 controls for about 10,000 single nucleotide polymorphisms (SNPs) and confirm important SNPs in a new group of subjects . We will (1) use functional genomic and bioinformatic tools (e.g. GenMAPP, SIFT , HapMap) to interrogate and integrate genomic and function databases to select SNPs based on clearly defined prioritization criteria (validated, non-synonymous coding or other functional SNPs with allele frequency >5% prioritized for candidate chromosomal regions, genes and pathways potentially relevant to glioma pathogenesis with the remaining spanning the genome); (2) using genotyping results from the 10,000 SNPs, identify 400-1500 SNPs potentially associated with case control status (logistic regressions), case survival (Cox regressions), and age at case diagnosis (analyses of variance) using permutation tests to identify subsets of SNPs with low false discovery rates and other modeling methods such as Random Forests, logic regression and genomic tools to define interacting SNPs and enhance true discovery; (3) (a) accrue another 950 (about 500 population based and 450 clinic based) glioma cases diagnosed from 5/06-12/09 and 500 population-based controls obtaining blood, buccal, and tumor specimens, and treatment and questionnaire data about family and personal medical histories, occupation, and dietary preferences, (b) classify tumors with neuropathology review and tumor markers (genetic and expression changes in p53 and EGFR), (c) conduct IgE and virologic IgG serologic studies, and (d) genotype the new astrocytic cases and controls for the previously identified SNPs (and other SNPs that may be in strong linkage disequilibrium with them); and (4) integrate SNP, demographic, environmental, immunologic, treatment and tumor data as appropriate to determine factors related to glioma etiology and prognosis. Public health significance: Primary brain cancers kill about 13,000 Americans a year; they rank first among all cancer sites for a verage years of life lost; little progress has been made in improving glioblastoma survival in over 30 years; this study will help identify factors that cause these cancers and that may predict survival. Enhanced understanding of these factors may provide targets for future interventions.