Genetic and molecular epidemiology of adult glioma

描述（由申请人提供）：神经胶质瘤是一种使人衰弱，通常迅速致命的癌症。最近的两项全基因组关联研究，包括我们小组的一项研究，发现并证实了三个区域与胶质母细胞瘤和其他高级别胶质瘤的风险相关，另外两个区域可能与低级别胶质瘤的风险相关。两个胶质瘤风险基因TERT和RTEL1与端粒维持有关。染色体9p21第三个危险区域（通常在胶质母细胞瘤中缺失）的多态性（snp）表明细胞周期基因CDKN2B的变异在胶质瘤形成中起作用。这代表了神经胶质瘤的第一个一致且高度重要的遗传风险因素，为神经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神经胶质瘤研究的第五个资助周期奠定了基础。在这项应用中，我们建立在我们广泛的数据和生物标本库的基础上，并通过胶质瘤国际病例对照研究（R01CA139020）在我们的站点继续招募成人胶质瘤病例和对照。具体目的是：(1)研究患者基因型风险谱与胶质瘤有意义的组织学和分子亚型（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本体论状态）的相关性。(2)对CDKN2B （9p21）、TERT、RTEL1、体外或模型系统以及来自流行病学招募的细胞培养分离物（淋巴细胞）中的胶质瘤风险snp进行功能基因组实验，并使用生物信息学分析来发现snp对转录因子结合或基因功能破坏的影响。(3)通过星形细胞胶质瘤病例和对照组端粒相关基因的基因分型和综合候选snp分析，深入研究所有已知端粒相关基因遗传变异与胶质瘤风险的关系。除了作为最近资助的神经胶质瘤国际病例控制研究和脑肿瘤孢子项目的一部分，我们现有的生物库和来自该资助的前20年研究的数据减少了这项拟议研究的成本。我们正在与其他胶质瘤研究人员积极合作，确保结果的协调和统一，并最大限度地提高快速翻译的机会。

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.