Deciphering Germline and Somatic Genomic Landscape of Gliomas in Black and Hispanic Minority Groups

摘要：项目3 最近的基因组图谱，包括癌症基因组图谱，已经极大地澄清了分子 恶性胶质瘤的基础。然而，这些开创性研究中使用的大多数样本集 来自白人或东亚患者。目前对体细胞和生殖系知之甚少。 黑人或西班牙裔人群中的胶质瘤情况。此外，每年的发病率有显著差异 这些少数民族的胶质瘤相对于白人的临床表现强烈表明 这两个群体之间存在基本的和临床相关的遗传差异。与这一猜想一致， 我们最近发现，生殖系单核苷酸多态(SNPs)的模式与 按种族划分的胶质瘤，白人血统较高的黑人和西班牙裔美国人 与水平较低的人相比，发生胶质瘤的风险更大。我们还确定了一组独特的SNP，与 白人中与胶质瘤相关的SNPs，这似乎使黑人和西班牙裔美国人对胶质瘤易感性。这些 研究结果表明，一项更大规模的研究，专门探测了黑人的体细胞和生殖系分子图谱 和西班牙裔患者，将弥合关键的知识差距，为更优化、更个性化奠定基础 病人管理。这一建议的中心假设是，不同的遗传特征，生殖系和 黑人和拉美裔人的躯体因素对IDH突变和IDH野生型胶质瘤的风险和临床预后的影响 子组。我们将结合生殖系SNP数据和广泛的基因组图谱分析病例匹配的肿瘤 迄今为止最大的、有临床注释的少数族裔患者队列。我们的具体目标将体现在 黑人和西班牙裔患者脑胶质瘤的基因组图谱，2)决定了种族 黑人和西班牙裔美国人的成分与定义疾病的分子变化相关，以及3)评估 黑人和西班牙裔的生殖系和体细胞变异对临床结果的影响程度。我们的工作将 阐明黑人和西班牙裔人群中胶质瘤的体细胞和生殖系遗传学，并在此过程中，解决 该领域的主要知识缺口。我们还将在与祖先相关的 生殖系遗传学、分子特异性的胶质瘤亚型和临床结果，提供了对 胶质瘤在不同种族的患者群体中产生和表现的机制。这些发现 既应该为治疗发展提供信息，也应该促进优化患者管理的设计。

SUMMARY: PROJECT 3 Recent genomic profiling, including that of the Cancer Genome Atlas, has greatly clarified the molecular foundations of malignant glioma. However, most of the sample sets employed in these groundbreaking studies were derived from White or East Asian patients. Very little is currently known about the somatic and germline landscapes of gliomas in Black or Hispanic populations. Moreover, significant differences in the annual incidence and clinical performance of gliomas in these minorities relative to those of Whites strongly suggests that fundamental and clinically-relevant genetic distinctions exist between the groups. Consistent with this conjecture, we recently found that patterns of germline single nucleotide polymorphisms (SNPs) differentially associated with glioma by ethnic group and that Blacks and Hispanics with a higher level of White ancestry had a greater risk for glioma development than those with lower levels. We also identified a unique set of SNPs, distinct from glioma-associated SNPs in Whites, that appear to confer glioma susceptibility in Blacks and Hispanics. These findings indicate that a larger study, probing both somatic and germline molecular profiles exclusively in Black and Hispanic patients, would bridge crucial knowledge gaps, setting the stage for more optimized, individualized patient management. The central hypothesis of this proposal is that distinct genetic features, germline and somatic, in Blacks and Hispanics influence risk and clinical prognosis in IDH-mutant and IDH-wild type glioma subgroups. We will combine germline SNP data with extensive genomic profiling in case-matched tumors from the largest, clinically-annotated minority patient cohort assembled to date. Our specific aims will 1) characterize the genomic landscape of glioma in Black and Hispanic patients, 2) determine the extent to which ethnic composition in Blacks and Hispanics correlates with disease-defining molecular alterations, and 3) evaluate the extent to which germline and somatic variation in Blacks and Hispanics impacts clinical outcome. Our work will clarify the somatic and germline genetics of glioma in Black and Hispanic populations and in doing so, address a major knowledge gap in the field. We will also establish robust correlations between ancestry-associated germline genetics, molecularly-specified glioma subclasses, and clinical outcome, providing insights into the mechanisms by which gliomas arise and behave in patient populations of differing ethnicity. These findings should both inform therapeutic development and facilitate the design of optimized patient management.