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

基本信息

批准号：
10393052
负责人：
MELISSA L. BONDY
金额：
$ 82.94万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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/10393052
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 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 Susceptibility Gene Syndrome TP53 gene Technology Testing Tumor Subtype Tumor Suppressor Proteins Untranslated RNA Validation Variant Work cohort disorder risk gene discovery genetic testing genome sequencing high risk in vivo innovation inquiry-based learning 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

项目摘要

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.

抽象的遗传易感性在神经胶质瘤发育中起着重要作用。一个或两个或多个的个人和/或二级影响的亲戚的疾病风险增加了两倍。我们是第一个建议的人 POT1中的突变（保护端粒1）是家族性神经胶质瘤（FG）的致病性。我们现在已经建立了 5个不同家族中POT1突变的存在，提供了其在神经胶质瘤中作用的最有力的证据。但是，我们尚未有直接的功能证据表明，POT1的损失是神经瘤的因果载体监视或潜在治疗目标的选项。我们目前能够解释遗传基础多达12％的家庭的神经胶质瘤，使用高度严格的标准来称突变有害和因果。相比之下，尽管几个候选基因具有出现为“感兴趣的嫌疑人（SOIS）”。我们提出了一种基于数据驱动的，基于知识的计算方法，以指导候选基因选择功能表征。为了促进我们为解释FG的遗传基础的努力，我们提出了两个具体目的是：确定可能通过WG导致FG的新基因候选者（AIM 1）。我们将确定基因组的编码和非编码区域中的SNV，小插入和结构变体，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他们引起疾病的可能性。除了有270例FG病例（来自203 FG家庭）序列数据已经可用，我们还将为另外100例（来自100个家庭）序列在我们的神经胶质瘤国际病例对照研究中收集了使用神经元标准的家族史，还有200例新招募的病例（来自100个家庭）具有良好家族瘤的家族史，以增强我们的发现。）。如果可以分析我们的队列，我们将分子表征肿瘤样品按肿瘤亚型。第二个目的是在功能上验证sois包括：a）在其他家庭和b）来自AIM 1的新发现的FG易感基因（SOI）使用我们的小说实验性小鼠干细胞球和胶质性的小鼠模型。确定功能在我们的WGS研究中确定的POT1和新型突变的贡献，我们将评估这些基因 Glioma小鼠模型使用CRISPR基因编辑技术。这项研究具有描述神经胶质瘤的遗传基础的强大潜力。家庭；成功将提供有关神经胶质瘤的潜在生物学的见解，以供未来的早期检测和有针对性的治疗。