(PQ3) UNDERSTANDING THE INTERACTIONS BETWEEN GERMLINE AND SOMATIC ALTERATIONS in the PATHOGENESIS OF GLIOMAS

(PQ3) 了解胶质瘤发病机制中种系和体细胞改变之间的相互作用

基本信息

批准号：
10475617
负责人：
ROBERT B. JENKINS
金额：
$ 60.45万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-04 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475617
关键词：
19q Address Adult Age of Onset Binding Blood Brain Caring Cell Line Cells Central Nervous System Neoplasms Characteristics Classification Clinic Clinical Clinical Data Clinical Management DNA Methylation DNA Sequence Alteration Data Development Diffuse Engineering Etiology Evolution Family history of Genes Genetic Genomics Germ-Line Mutation Glioma Human Lesion Maps Methods Modeling Molecular Molecular Genetics Mutate Mutation Odds Ratio Pathogenesis Patient risk Patient-Focused Outcomes Patients Phenotype Predisposition Public Health Publishing Research Risk Risk Assessment Seizures Somatic Mutation TP53 gene Testing Translating Variant Work base cell type clinical practice clinically relevant cost epigenome functional genomics genome wide association study global run on sequencing high risk population histone modification molecular subtypes mutant novel novel therapeutic intervention outcome prediction promoter risk variant transcription factor transcriptome transcriptome sequencing tumor

项目摘要

Provocative Question 3: Summary/Abstract This proposal addresses Provocative Question #3, “Do genetic interactions between germline variants and somatic mutations contribute to differences in tumor evolution?” The new 2016 WHO Classification of Tumors of the Central Nervous System utilizes two somatic alterations to molecularly classify adult diffuse glioma: IDH mutation and 1p/19q codeletion. We and others have shown that TERT promoter mutation further classifies gliomas into molecular subtypes with distinct clinical characteristics. In addition, during the last five years much has been learned about the germline predisposition to gliomas: genome-wide association studies (GWAS) have revealed that 25 regions in 24 genes are associated with glioma development. Our group identified many of these associations and fine-mapped two of them (MYC/CCDC26 and TP53) and demonstrated that the MYC/CCDC26 variant (rs55705857) is associated with IDH-mutant gliomas. Indeed we found rs55705857 to have an odds ratio>6 for development of IDH-mutated glioma and lowers the age of onset by ~10 years. It is clear that the risk allele of rs55705857 interacts with somatic IDH-mutation to accelerate low-grade glioma development. We hypothesize that germline variants interact with somatic alterations to accelerate the development of IDH-mutant and IDH wild-type gliomas. Our published and preliminary data provide strong evidence in support of this hypothesis; but it must be explored further. While each of the known 25 regions has been evaluated with respect to risk of the 2016 WHO molecular subtypes, an unbiased GWAS has yet to be performed. Thus, Aim 1 will cost- effectively utilize previously-collected GWAS data to identify novel germline variants that are associated with the WHO subtypes in order to provide better patient risk assessment. Aim 2 will translate these findings into the clinic by integrating the germline and somatic alterations to determine associations with patient survival. Lastly, Aim 3 will use functional genomics to begin to understand the mechanisms by with rs55705857 and other variants accelerate IDH-mutant glioma.

挑衅性问题 3：总结/摘要该提案解决了挑衅性问题#3：“基因之间是否存在相互作用？种系变异和体细胞突变导致肿瘤进化的差异？” 2016 年新的 WHO 中枢神经系统肿瘤分类采用了两种分类用于对成人弥漫性胶质瘤进行分子分类的体细胞改变：IDH 突变和 1p/19q 我们和其他人已经证明 TERT 启动子突变可以进一步对神经胶质瘤进行分类。此外，在过去的五年中，它们被分为具有不同临床特征的分子亚型。关于神经胶质瘤的种系易感性已经了解很多：全基因组关联研究（GWAS）揭示24个基因的25个区域与神经胶质瘤相关我们的小组确定了其中许多关联，并详细绘制了其中两个关联。（MYC/CCDC26 和 TP53）并证明 MYC/CCDC26 变体（rs55705857）是事实上，我们发现 rs55705857 的比值比 >6。 IDH 突变神经胶质瘤的发展并使发病年龄降低约 10 岁。 rs55705857 的风险等位基因与体细胞 IDH 突变相互作用，加速低级别胶质瘤的发生我们已经探索了种系变异与体细胞改变的相互作用。加速 IDH 突变型和 IDH 野生型神经胶质瘤的发展。初步数据为支持这一假设提供了强有力的证据；但必须对其进行探索；此外，已知的 25 个地区均已针对 2016 年的风险进行了评估。 WHO 分子亚型，公正的 GWAS 尚未实施，因此，目标 1 的成本将是 - 有效利用先前收集的 GWAS 数据来识别新的种系变异与 WHO 亚型相关联，以便提供更好的患者风险评估。通过将种系和体细胞的改变整合到最后，目标 3 将使用功能基因组学来开始。了解 rs55705857 和其他变体加速 IDH 突变的机制神经胶质瘤。