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: 7814535
• 负责人: ROBERT B. JENKINS
• 金额: $ 49.78万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7814535
• 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）：此申请涉及广泛的挑战领域（08）基因组学和特定挑战主题08-CA-101*增强全基因组关联研究。假设胶质母细胞瘤（GBM）的发展与相对常见的生殖线改变有关，而渗透率有限。与加利福尼亚大学旧金山大学（UCSF）的小组合作，我们最近报道说，SNP映射到9p和20q与GBM的发展有关。我们建议表征这9p和20q区域内的种系改变，并将其与Glioma 9p缺失和20Q增益相关。具体目标1：使用1200例和对照对相关的9P和20Q区域进行详细的种系遗传分析，以确定已知多态性和新改变的患病率。 AIM 1A：对所有非冗余SNP的600例先前基因型病例和匹配的对照进行自定义基因分型，以更好地定义单倍型。估算Hapoytpes并评估他们与GBM开发的关联。 AIM 1B：在50 GBM病例和50个携带估算的高风险单倍型的对照中，分别对9p和20内的〜200KB和〜100KB区域进行高通量测序。为了直接确定单倍型结构，请对50个孤立的高危和非风险染色体进行高通式测序。 AIM 1C：在600例新病例中定制基因型候选多态性，并匹配的控件以验证AIMS 1A和1B的新变化。 AIM 1D：对9P和20Q区域进行自定义ACGH分析以确定拷贝数变体。具体目标2：对案例进行神经胶质瘤的详细遗传分析和表达分析。 AIM 2A：使用鱼类和自定义CGHA定义神经胶质瘤9P缺失和20q增益状态。 AIM 2B：序列9p和20q区域中的所有外显子。评估靶基因启动子的甲基化。 AIM 2C：评估目标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。特定目标3：将多态性/变化/单倍型患病率差异以及获得的神经胶质瘤改变相关联，以产生候选种系9P和20Q突变的列表，可能与神经胶质瘤的发展有关。神经胶质瘤会引起明显的发病率和死亡率。每年约有18,500人被诊断出患有神经胶质瘤。由于大多数神经胶质瘤在生物学上都是侵略性的，因此美国大约有12,800人每年屈服于这些肿瘤。了解神经胶质瘤的易感性将对预防神经胶质瘤以及对这些肿瘤的治疗产生重大影响。