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

发人深省的问题3：摘要/摘要 这项提议解决了令人不快的问题#3，“基因之间是否存在相互作用 生殖系变异和体细胞突变会导致肿瘤进化的差异吗？ 2016年世卫组织新的中枢神经系统肿瘤分类使用了两个 成人弥漫性胶质瘤分子分类的体细胞改变：IDH突变和1p/19q 共删除。我们和其他人已经证明，TERT启动子突变可以进一步对胶质瘤进行分类 形成具有鲜明临床特征的分子亚型。此外，在过去的五年中， 关于神经胶质瘤的生殖系易感性：全基因组关联已有很多研究 研究表明，24个基因中的25个区域与胶质瘤有关。 发展。我们的小组确定了其中的许多关联，并对其中的两个进行了精细绘制 (MYC/CCDC26和TP53)，并证明了MYC/CCDC26变体(Rs55705857)是 与IDH突变的胶质瘤有关。事实上，我们发现rs55705857的赔率为 IDH突变的胶质瘤的发生和发病年龄降低了约10岁。很明显， Rs55705857易感等位基因与体细胞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变化相互作用 加速IDH突变型和IDH野生型胶质瘤的发展。我们出版的和 初步数据为支持这一假设提供了强有力的证据；但它必须加以探索 再远一点。虽然已知的25个地区中的每一个都已就2016年的风险进行了评估 世卫组织的分子亚型，一个公正的GWA型尚未进行。因此，目标1将花费- 有效地利用之前收集的Gwas数据来识别新的生殖系变异，这些变异 与世卫组织亚型相关联，以便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变化将这些发现转化为临床 确定与患者生存的关联。最后，Aim 3将使用功能基因组学开始 用rs55705857和其他变异体加速idh突变体以了解其机制 神经胶质瘤。

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.