Discovery, Biology and Risk of Inherited Variants in Glioma

神经胶质瘤遗传变异的发现、生物学和风险

• 批准号: 10239259
• 负责人: MELISSA L. BONDY
• 金额: $ 98.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10239259
• 关键词: Affect; Alleles; Animal Model; Biological; Biological Assay; Biology; Breast; Candidate Disease Gene; Case-Control Studies; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Colorectal; Data; Data Sources; Development; Diagnosis; Disease; Early Diagnosis; Etiology; European; Event; Family; Family Study; Family history of; Family member; Future; Gender; Gene Mutation; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genome; Glioma; Gliomagenesis; Goals; Hereditary Malignant Neoplasm; In Vitro; Incidence; Individual; Inherited; International; Knowledge; Lead; Length; Malignant Glioma; Malignant Neoplasms; Mendelian disorder; Molecular; Mus; Mutation; NF1 gene; Pathway interactions; Patients; Penetrance; Play; Population; Predisposition; Recording of previous events; Reporting; Research; Resources; Risk; Role; Sample Size; Sampling; Structure; Susceptibility Gene; Syndrome; TP53 gene; Technology; Testing; Tumor Subtype; Tumor Suppressor Proteins; Untranslated RNA; Validation; Variant; Work; base; cohort; disorder risk; gene discovery; genetic testing; genetic variant; genome sequencing; high risk; in vivo; innovation; insertion/deletion mutation; insight; interest; knowledge base; mouse model; novel; proband; rare cancer; rare condition; rare variant; recruit; screening; stem cells; success; targeted treatment; telomere; tumor; tumorigenesis; whole genome

ABSTRACT Genetic susceptibility plays a significant role in glioma development. An individual with two or more first- and/or second-degree affected relatives has a two-fold increased risk of the disease. We were the first to suggest mutations in POT1 (Protection of Telomeres 1) as causative in familial glioma (FG). We have now established the presence of POT1 mutations in 5 different families, providing the strongest evidence of its role in glioma. However, we do not yet have direct functional evidence that loss of POT1 is causal in glioma leaving few options for carrier surveillance or potential treatment targets. We are currently able to explain the genetic basis of glioma in up to 12% of our families, using highly stringent criteria for calling a mutation deleterious and causal. In contrast, the majority of our families remain unexplained though several candidate genes have emerged as `suspects of interest (SOIs)'. We propose a data-driven, knowledge-based, computational approach to guide candidate gene selection for functional characterization. In order to further our efforts to explain the genetic basis of FG we propose two specific aims to: Identify new gene candidates that may cause FG through WGS (Aim 1). We will identify SNVs, small indels, and structural variants in both coding and noncoding regions of the genome, intensively annotate those variants using more than 50 data sources, and we will rank these variants using multiple criteria based on their likelihood to cause disease. In addition to the 270 FG cases (from 203 FG families) with sequence data already available, we will also sequence an additional 100 cases (from 100 families) already collected in our Glioma International Case-Control Study with a reported family history using Gliogene criteria, and 200 newly recruited cases (from 100 families) with a strong family history of glioma to enhance our discovery. ). We will molecularly characterize tumor samples when available to enable analysis of our cohort by tumor subtype. The second aim is to functionally validate SOIs to include: A) POT1 mutations identified in additional families and B) newly discovered FG susceptibility genes (SOIs) from Aim 1 using our novel experimental mouse stem cell spheres and mouse models of gliomagenesis.To determine the functional contributions of POT1 and novel mutations identified in our WGS studies, we will evaluate these genes in glioma mouse models using CRISPR gene editing technology. This study has the strong potential for delineating the genetic basis of glioma for genetic testing of high-risk families; success will offer insight on the underlying biology of glioma for future work on early detection and targeted treatment.

摘要 遗传易感性在脑胶质瘤的发生发展中起着重要作用。个人有两个或更多的第一和/或 受二级影响的亲属患这种疾病的风险增加了两倍。我们是第一个建议 POT1(端粒保护1)突变是家族性胶质瘤(FG)的致病因素。我们现在已经建立了 POT1突变在5个不同的家系中的存在，为其在胶质瘤中的作用提供了最有力的证据。 然而，我们还没有直接的功能证据表明POT1的丢失是神经胶质瘤的原因，只剩下很少的 针对携带者监视或潜在治疗目标的选项。我们目前能够解释遗传基础 在我们高达12%的家庭中，使用非常严格的标准将突变称为有害和 因果关系。相比之下，我们大多数家庭仍然无法解释，尽管有几个候选基因 成为“可疑嫌犯(SOI)”。 我们提出了一种数据驱动的、基于知识的计算方法来指导候选基因选择 功能特性。为了进一步解释FG的遗传基础，我们提出了两个 具体目标是：通过WGS确定可能导致FG的新候选基因(目标1)。我们将确定 SNV、小Indels和基因组编码区和非编码区的结构变体 使用50多个数据源注释这些变体，我们将使用多个标准对这些变体进行排名 基于它们引发疾病的可能性。除270个FG病例(来自203个FG家庭)外， 测序数据已经可用，我们还将对另外100个病例(来自100个家庭)进行测序 收集在我们的国际胶质瘤病例对照研究中，并报告了使用Gliogene标准的家族史， 和200例新招募的病例(来自100个家庭)，有很强的胶质瘤家族史，以加强我们的 发现号。)。当肿瘤样本可用时，我们将对肿瘤样本进行分子特征分析，以便对我们的队列进行分析 按肿瘤亚型分类。第二个目标是从功能上验证SOI，以包括：a)在 其他家族和B)利用我们的新发现的FG易感基因(SOI)来自AIM 1 实验小鼠干细胞球和小鼠胶质瘤模型。 在我们的WGS研究中发现的POT1和新突变的贡献，我们将在 采用CRISPR基因编辑技术建立小鼠脑胶质瘤模型。 这项研究有很强的潜力来描绘胶质瘤的遗传学基础，用于高危基因检测。 家庭；成功将提供对胶质瘤潜在生物学的洞察，为未来的早期发现和 有针对性的治疗。