Identification of 9p and 20q Germline Alterations in Glioblastoma Pathogenesis

胶质母细胞瘤发病机制中 9p 和 20q 种系改变的鉴定

• 批准号: 7937827
• 负责人: ROBERT B. JENKINS
• 金额: $ 48.61万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937827
• 关键词: 20q; Accounting; Address; Applications Grants; Area; California; Cancer Family; Candidate Disease Gene; Chromosomes; Control Groups; Custom; Development; Diagnosis; Disease; Epidermal Growth Factor Receptor; Exons; Family; Fluorescent in Situ Hybridization; Gene Targeting; Genetic; Genetic Polymorphism; Genomics; Genotype; Glioblastoma; Glioma; Haplotypes; Hereditary Melanoma; Learning; Methylation; Molecular Profiling; Morbidity - disease rate; Mus; Mutation; PTEN gene; Pathogenesis; Penetrance; Phase; Predisposition; Prevalence; Prevention; Reporting; Risk; San Francisco; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Specimen; Structure; Syndrome; Technology; Universities; Variant; case control; chromosome 20 gain; chromosome 7 gain; comparative genomic hybridization; genetic analysis; genome wide association study; mortality; promoter; tumor

DESCRIPTION (provided by the applicant): This application addresses broad Challenge Area (08) Genomics, and specific Challenge Topic 08-CA-101* Augmenting Genome-Wide Association Studies. The development of glioblastoma (GBM) has been hypothesized to be associated with relatively common germline alterations with limited penetrance. Collaborating with the group at the University of California at San Francisco (UCSF) we recently reported that SNPs mapping to 9p and 20q are associated with the development of GBM. We propose to characterize the germline alterations within these 9p and 20q regions and to correlate these with glioma 9p deletion and 20q gain. Specific Aim 1: Perform detailed germline genetic analysis of the associated 9p and 20q regions using 1200 cases and controls to determine the prevalence of known polymorphisms and new alterations. Aim 1a: Perform custom genotyping of 600 previously genotyped cases and matched controls for all non-redundant SNPs to better define haplotypes. Impute haploytpes and evaluate their association with GBM development. Aim 1b: Perform high-throughput sequencing of the ~200kb and ~100kb regions within 9p and 20, respectively, in 50 GBM cases and 50 controls that carry the imputed at-risk haplotypes. To directly determine haplotype structure, perform high-through-put sequencing of 50 isolated at-risk and non-risk chromosomes. Aim 1c: Custom genotype candidate polymorphisms in 600 new cases and matched controls to validate new alterations from Aims 1a and 1b. Aim 1d: Perform custom aCGH analysis of the 9p and 20q regions to ascertain copy number variants. Specific Aim 2: Perform detailed genetic analysis and expression analysis of gliomas from the cases. Aim 2a: Using FISH and custom CGHa define glioma 9p deletion and 20q gain status. Aim 2b: Sequence all exons in the 9p and 20q regions. Assess methylation of target gene promoters. Aim 2c: Evaluate the tumor expression of all known exons and miRNAs within the targeted regions. Determine the underlying GBM genetic subtype. Specific Aim 3: Correlate polymorphism/ alteration/haplotype prevalence differences and with acquired glioma alterations to generate a list of candidate germline 9p and 20q mutations likely to be associated with the development of gliomas. Gliomas cause significant morbidity and mortality. Approximately 18,500 people in the U.S. are diagnosed with glioma each year. Because most gliomas are biologically aggressive, approximately 12,800 people in the U.S. succumb to these tumors every year. Understanding the predisposition to gliomas will have major implications for the prevention of gliomas as well as the management of these tumors.

描述（由申请人提供）：本申请涉及广泛的挑战领域（08）基因组学和特定的挑战主题08-CA-101* 增强全基因组关联研究。胶质母细胞瘤（GBM）的发生被认为与相对常见的生殖系改变有关，但其发生率有限。我们最近与位于旧金山弗朗西斯科的加州大学（UCSF）的研究小组合作，报道了定位于9 p和20 q的SNP与GBM的发生有关。我们建议在这些9 p和20 q区域内的种系改变的特征，并将这些与胶质瘤9 p缺失和20 q增益。具体目标1：使用1200例病例和对照对相关的9 p和20 q区域进行详细的生殖系遗传分析，以确定已知多态性和新变异的患病率。目的1a：对600例先前基因分型的病例和所有非冗余SNP的匹配对照进行定制基因分型，以更好地定义单倍型。植入单倍型并评估其与GBM发育的相关性。目标1b：对50例携带插补风险单倍型的GBM病例和50例对照中分别在9 p和20内的~ 200 kb和~ 100 kb区域进行高通量测序。为了直接确定单倍型结构，对50个分离的风险和非风险染色体进行高通量测序。目的1c：在600例新病例和匹配对照中定制基因型候选多态性，以验证目的1a和1b的新改变。目的1d：对9 p和20 q区域进行定制aCGH分析，以确定拷贝数变体。具体目标2：对病例中的胶质瘤进行详细的基因分析和表达分析。目的2a：使用FISH和定制CGHa确定胶质瘤9 p缺失和20 q获得状态。目的2b：对9 p和20 q区域中的所有外显子进行测序。评估靶基因启动子的甲基化。目的2c：评估靶区域内所有已知外显子和miRNA的肿瘤表达。确定潜在的GBM遗传亚型。具体目标3：将多态性/改变/单倍型患病率差异与获得性胶质瘤改变相关联，以生成可能与胶质瘤发展相关的候选生殖系9 p和20 q突变列表。神经胶质瘤引起显著的发病率和死亡率。美国每年约有18，500人被诊断患有神经胶质瘤。由于大多数神经胶质瘤具有生物侵袭性，美国每年约有12，800人死于这些肿瘤。了解神经胶质瘤的易感性将对神经胶质瘤的预防以及这些肿瘤的管理具有重要意义。