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

问题三：摘要/Abstract 该提案解决了挑衅性问题#3，“基因之间的相互作用是否 生殖系变异和体细胞突变有助于肿瘤演变的差异？” 新的2016年WHO中枢神经系统肿瘤分类采用了两种 成人弥漫性胶质瘤分子分类体细胞改变：IDH突变和1 p/19 q 共缺失我们和其他人已经表明，TERT启动子突变进一步分类胶质瘤 分为不同临床特征的分子亚型。此外，在过去五年中， 关于神经胶质瘤的生殖系易感性已经了解了很多：全基因组关联 研究（GWAS）已经揭示24个基因中的25个区域与胶质瘤相关 发展我们的研究小组确定了许多这样的关联，并对其中两个进行了精细的映射 (MYC/CCDC 26和TP 53），并证明MYC/CCDC 26变体（rs 55705857）是 与IDH突变神经胶质瘤有关事实上，我们发现rs 55705857对于 IDH突变的神经胶质瘤的发展，并降低发病年龄约10年。很明显 rs 55705857危险等位基因与体细胞IDH突变相互作用加速低级别胶质瘤 发展我们假设生殖系变异与体细胞改变相互作用， 加速IDH突变型和IDH野生型神经胶质瘤的发展。我们的出版和 初步数据提供了强有力的证据支持这一假设，但必须加以探讨 进一步.虽然已知的25个地区中的每一个都已经就2016年的风险进行了评估， 世界卫生组织分子亚型，一个公正的GWAS尚未进行。因此，目标1将花费- 有效地利用先前收集的GWAS数据来鉴定新的种系变异， 与WHO亚型相关，以提供更好的患者风险评估。目标2将 通过整合生殖系和体细胞改变， 确定与患者生存率的关系。最后，目标3将使用功能基因组学开始 通过rs 55705857等变异体加速IDH突变的机制 胶质瘤

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.