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:10239259
- 负责人:
- 金额:$ 98.9万
- 依托单位:
- 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:
- 关键词:AffectAllelesAnimal ModelBiologicalBiological AssayBiologyBreastCandidate Disease GeneCase-Control StudiesClustered Regularly Interspaced Short Palindromic RepeatsCodeColorectalDataData SourcesDevelopmentDiagnosisDiseaseEarly DiagnosisEtiologyEuropeanEventFamilyFamily StudyFamily history ofFamily memberFutureGenderGene MutationGeneral PopulationGenesGeneticGenetic Predisposition to DiseaseGenetic studyGenomeGliomaGliomagenesisGoalsHereditary Malignant NeoplasmIn VitroIncidenceIndividualInheritedInternationalKnowledgeLeadLengthMalignant GliomaMalignant NeoplasmsMendelian disorderMolecularMusMutationNF1 genePathway interactionsPatientsPenetrancePlayPopulationPredispositionRecording of previous eventsReportingResearchResourcesRiskRoleSample SizeSamplingStructureSusceptibility GeneSyndromeTP53 geneTechnologyTestingTumor SubtypeTumor Suppressor ProteinsUntranslated RNAValidationVariantWorkbasecohortdisorder riskgene discoverygenetic testinggenetic variantgenome sequencinghigh riskin vivoinnovationinsertion/deletion mutationinsightinterestknowledge basemouse modelnovelprobandrare cancerrare conditionrare variantrecruitscreeningstem cellssuccesstargeted treatmenttelomeretumortumorigenesiswhole 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.
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MELISSA L. BONDY其他文献
MELISSA L. BONDY的其他文献
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{{ truncateString('MELISSA L. BONDY', 18)}}的其他基金
The Upstream Center: Income Interventions to Address the Fundamental Causes of Cancer Inequities
上游中心:解决癌症不平等根本原因的收入干预措施
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10661407 - 财政年份:2023
- 资助金额:
$ 98.9万 - 项目类别:
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:
10393052 - 财政年份:2020
- 资助金额:
$ 98.9万 - 项目类别:
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:
10143088 - 财政年份:2020
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9590487 - 财政年份:2018
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Risk Prediction for ER Negative Breast Cancer Recurrence
ER 阴性乳腺癌复发的风险预测
- 批准号:
8786997 - 财政年份:2013
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Risk Prediction for ER Negative Breast Cancer Recurrence
ER 阴性乳腺癌复发的风险预测
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8420149 - 财政年份:2013
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Risk Prediction for ER Negative Breast Cancer Recurrence
ER 阴性乳腺癌复发的风险预测
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9198211 - 财政年份:2013
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