Genetic and Molecular Epidemiology of Adult Glioma

描述（由申请人提供）：恶性神经胶质瘤通常是使人衰弱的、迅速致命的癌症。影响胶质瘤病因或预后的一致因素很少，可能是由于组织学类型内和组织学类型之间因果和进展途径的异质性。许多研究表明遗传易感性和环境及免疫因素在胶质瘤形成中的作用。遗传变异和肿瘤标志物也可能影响生存，除了既定的因素，如年龄，放射治疗和切除。这项建议建立在15年的研究，以增加了解这些和其他因素与成人胶质瘤的病因和预后之间的良好特征的病例和对照。在这两个阶段的研究中，我们将基因型组成DNA从900个现有的星形胶质细胞病例和700个对照约10,000单核苷酸多态性（SNP），并确认重要的SNP在一组新的主题。我们将（1）使用功能基因组学和生物信息学工具（例如GenMAPP、SIFT、HapMap）来询问和整合基因组和功能数据库，以基于明确定义的优先级标准来选择SNP（对于候选染色体区域优先考虑等位基因频率>5%的经验证的非同义编码或其他功能性SNP，与神经胶质瘤发病机制潜在相关的基因和途径，其余跨越基因组）;（2）使用来自10，000个SNP的基因分型结果，鉴定400-1500个可能与病例对照状态相关的SNP（logistic回归），病例生存率（考克斯回归）和病例诊断时的年龄（方差分析）使用置换检验来鉴定具有低错误发现率的SNP子集，以及其他建模方法，例如随机森林，逻辑回归和基因组工具来定义相互作用的SNP并增强真正的发现;（3）（a）增加950（约500个基于人群和450个基于诊所）从5/06-12/09诊断的神经胶质瘤病例和500个基于人群的对照，获得血液、口腔和肿瘤标本，以及治疗和关于家族和个人病史、职业，和饮食偏好，（B）用神经病理学回顾和肿瘤标志物对肿瘤进行分类（p53和EGFR的遗传和表达变化），（c）进行IgE和病毒学IgG血清学研究，和（d）对新的星形胶质细胞病例和对照进行先前鉴定的SNP的基因分型（以及其他可能与它们处于强连锁不平衡的SNP）;和（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学和预后相关的因素。公共卫生意义：原发性脑癌每年导致约13，000名美国人死亡;他们在所有癌症部位中排名第一，失去了20年的生命;在30多年的时间里，在改善胶质母细胞瘤生存方面几乎没有取得进展;这项研究将有助于确定导致这些癌症的因素，并可能预测生存。 加强对这些因素的了解可能为今后的干预提供目标。

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.