Genetic and molecular epidemiology of adult glioma

描述(申请人提供)：胶质瘤是一种衰弱的，通常是迅速致命的癌症。最近的两项全基因组关联研究，包括我们团队的一项研究，发现并确认了三个与胶质母细胞瘤和其他高级别胶质瘤风险相关的区域，以及另外两个可能与低级别胶质瘤风险相关的区域。两个胶质瘤风险基因，TERT和RTEL1，与端粒维持有关。染色体9p21第三危险区域的SNPs(在胶质母细胞瘤中常见缺失)提示细胞周期基因CDKN2B的变异在胶质瘤发生中的作用。这些代表了第一个一致和高度显著的胶质瘤遗传风险因素，为胶质瘤流行病学提供了一个全新的视角，并为我们旧金山湾区胶质瘤研究的第五个资助周期奠定了基础。在这一应用中，我们建立在我们广泛的数据和生物检验库以及通过胶质瘤国际病例对照研究(R01CA139020)支持的成人胶质瘤病例和对照的持续招募的基础上。其具体目的是：(1)检查患者的基因风险分布与有意义的胶质瘤的组织学和分子亚型的关系，包括IDH1和IDH2突变，P53和EGFR突变状态，以及与基因表达相关的脑肿瘤的本体状态。(2)利用生物信息学方法对CDKN2B(9p21)、TERT、RTEL1、体外或模型系统中的胶质瘤危险基因SNPs进行功能基因组学实验，并利用生物信息学分析发现SNPs对转录因子结合或基因功能破坏的影响。(3)通过对星形细胞胶质瘤患者和对照组端粒相关基因的一组候选SNPs进行基因分型和分析，对所有已知的端粒相关基因的遗传变异与胶质瘤风险的关系进行彻底的检查。除了是最近资助的胶质瘤国际病例对照研究和脑瘤孢子计划的一部分外，我们现有的生物库和这项赠款之前20年的研究数据还降低了这项拟议研究的成本。我们与其他胶质瘤研究人员的积极合作确保了结果的协调和统一，并最大限度地增加了快速翻译的机会。 与公共健康相关：美国人每年死于原发脑癌的人数约为1.3万人，在平均寿命损失年数上，它在所有癌症部位中排名第一。这项研究将有助于确定导致这些癌症的因素。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): Glioma is a debilitating, often rapidly fatal cancer. Two recent genome wide association studies including one by our group discovered and confirmed three regions associated with risk of glioblastoma and other high grade glioma, and two additional regions that are likely to be associated with risk of lower grade glioma. Two of the glioma risk genes, TERT and RTEL1, are related to telomere maintenance. Polymorphisms (SNPs) in a third risk region in chromosome 9p21 (commonly deleted in glioblastoma) suggest a role for variation in the cell cycle gene CDKN2B in gliomagenesis. These represent the first consistent and highly significant genetic risk factors for glioma which provide a completely new perspective on glioma epidemiology and form a basis for this fifth grant cycle of our San Francisco Bay Area Glioma Study. In this application, we build on our extensive data and biospecimen repository and continuing recruitment at our site of adult glioma cases and controls supported through the Glioma International Case Control Study (R01CA139020). The Specific Aims are to: (1) Examine associations of patients' genotypic risk profile with meaningful histologic and molecular subtypes of glioma including IDH1 and IDH2 mutations, P53 and EGFR mutation status, and the ontological status of brain tumors related to gene expression. (2) Perform functional genomic experiments for glioma risk SNPs in CDKN2B (9p21), TERT, RTEL1, in vitro or model systems and in cell culture isolates (lymphocytes) derived from our epidemiologic recruitment and use bioinformatic analyses to discover effects of SNPs on transcription factor binding or disruption of gene function. (3) Conduct a thorough examination of the association of inherited variation in all known telomere-related genes with glioma risk through genotyping and analysis of a comprehensive set of candidate SNPs in telomere related genes in astrocytic glioma cases and controls. In addition to being part of the recently funded Glioma International Case Control study and the brain tumor SPORE program, our existing biorepository and data from this grant's previous 20 years of studies reduce costs for this proposed study. Our ongoing active collaborations with other glioma researchers ensure coordination and harmonization of results and maximize opportunities for rapid translation. PUBLIC HEALTH RELEVANCE: Primary brain cancers kill about 13,000 Americans a year and rank first among all cancer sites for average years of life lost. This study will help identify factors that cause these cancers. Enhanced understanding of these factors may provide targets for future interventions.