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

挑衅性问题3：补充申请摘要/摘要 本补充申请是应特别利益通知的要求提交的 (NOSI)确定为NOT-CA-22-057，“加强全球癌症的行政补充剂 健康差距。“这是罗伯特·詹金斯博士的母公司R01项目的补充： 了解生殖系和体细胞变化在青光眼发病机制中的相互作用 神经胶质瘤(CA230712)，它是在回答挑衅性的问题#3时资助的 生殖系变异和体细胞突变之间的相互作用导致肿瘤的差异 进化论？“在2016年前，中枢神经系统(CNS)肿瘤的诊断基于 组织学特征。2016年，世界卫生组织(世卫组织)通过了一项诊断 将组织学外观与获得性分子改变相结合的方法。在2021年， 这些标准被更新了更多与不同大脑相关的分子标记 肿瘤亚型。非洲，进而是尼日利亚，由于各种原因在这一领域落后， 包括分子方法方面的技术诀窍有限和缺乏资源 以及对神经肿瘤学病例进行分子分析的设备。本副刊旨在 为了与过去九年中诊断的胶质瘤病例的组织学特征相匹配 拉各斯大学教学医院，尼日利亚拉各斯，具有分子签名。这项研究将是 这是尼日利亚第一次对胶质瘤进行分子研究，因此将使我们深入了解 尼日利亚中枢神经系统肿瘤的特征(包括获得性和生殖系分子改变)。 补充剂特定的Aim1将执行有针对性的临床测序和拷贝数分析 来自拉各斯大学教学医院的60名全球非洲胶质瘤研究对象。增刊 特定目标2将建立一个由全球非洲站点组成的合作联盟，以进一步研究 脑胶质瘤的获得性遗传学和种系遗传学。家长NCI挑衅性问题R01助学金(R01 CA230712)旨在评估生殖系和获得性遗传之间的相互作用 成人弥漫性胶质瘤的改变与生殖系变异相互作用的潜在假设 利用体细胞变化加速idh突变体和idh野生型的发育 神经胶质瘤。家长R01的具体目标是：家长特定目标1：识别小说 与临床定义的胶质瘤分子亚型相关的生殖系风险变异。 亲本特异性目标2：评价生殖系和体细胞相结合的临床相关性 与IDH突变型胶质瘤相关的改变。家长特定目标3：描述 已知和新发现的胶质瘤生殖系变异的功能意义 IDH突变的神经胶质瘤。因此，拟议的补充目标是对 通过将研究扩展到撒哈拉以南非洲的胶质瘤患者，为父母R01提供了帮助。

Provocative Question 3: Supplemental Application Summary/Abstract This supplement application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-22-057, “Administrative Supplements to Strengthen Global Cancer Health Disparities.” This is a supplement to the parent R01 project of Dr. Robert Jenkins: Understanding the interactions between germline and somatic alterations in the pathogenesis of gliomas (CA230712), which was funded in response to Provocative Question #3, “Do genetic interactions between germline variants and somatic mutations contribute to differences in tumor evolution?” Prior to 2016, the diagnosis of central nervous system (CNS) tumors was based on histologic features. In 2016, the World Health Organization (WHO) adopted a diagnostic approach that integrates histologic appearance with acquired molecular alterations. In 2021, these criteria were updated with many more molecular markers associated with various brain tumor subtypes. Africa, and by extension Nigeria, lags behind in this field for various reasons, including limited technical know-how in terms of molecular methods and the lack of resources and equipment to perform molecular analyses for neuro-oncology cases. This supplement aims to match the histologic characteristics of cases of gliomas diagnosed over the last nine years in Lagos University Teaching Hospital, Lagos Nigeria, with molecular signatures. This study will be the first molecular study of glioma in Nigeria, and therefore will give insight into the molecular features (including both acquired and germline molecular alterations) of CNS tumors in Nigeria. Supplement Specific Aim1 will perform targeted clinical sequencing and copy number profiling on 60 global African glioma subjects from Lagos University Teaching Hospital. Supplement Specific Aim 2 will build a collaborative consortium of global African sites to further study the acquired and germline genetics of glioma. The parent NCI Provocative Question R01 grant (R01 CA230712) is aimed at evaluating the interaction between germline and acquired genetic alterations in adult diffuse glioma with the underlying hypothesis that germline variants interact with somatic alterations to accelerate the development of IDH-mutant and IDH wild-type gliomas. The specific aims of the parent R01 are: Parent Specific Aim 1: To identify novel germline risk variants that are associated with clinically-defined glioma molecular subtypes. Parent Specific Aim 2: To evaluate the clinical relevance of combined germline and somatic alterations associated with IDH-mutant glioma. Parent Specific Aim 3: To characterize the functional implication of the known and newly identified glioma germline variants in the context of IDH-mutant glioma. Thus, the proposed supplement aims are a natural extension to the parent R01 by extending studies to patients with glioma in sub-Saharan Africa.