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

概要：项目3 最近的基因组分析，包括癌症基因组图谱，极大地阐明了分子生物学的作用。 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 来自白色或东亚患者。目前对体细胞和生殖细胞的了解很少， 在黑人或西班牙裔人群中的神经胶质瘤景观。此外，年发病率的显著差异 这些少数民族神经胶质瘤的临床表现与白人相比， 这两组之间存在基本的和临床相关的遗传差异。与这一推测一致， 我们最近发现，生殖系单核苷酸多态性（SNPs）的模式差异相关， 神经胶质瘤的发病率按种族分组，黑人和具有较高水平白色血统的西班牙裔人的发病率更高。 神经胶质瘤发展的风险高于那些水平较低的人。我们还发现了一组独特的SNP， 在白人中，神经胶质瘤相关的SNP似乎赋予了黑人和西班牙裔人神经胶质瘤的易感性。这些 研究结果表明，一个更大的研究，探测体细胞和生殖细胞的分子概况专门在黑色 和西班牙裔患者，将弥合关键的知识差距，为更优化，个性化 病人管理这一建议的中心假设是，不同的遗传特征，种系和 体细胞、黑人和西班牙裔影响IDH突变型和IDH野生型胶质瘤的风险和临床预后 分组。我们将联合收割机将生殖系SNP数据与来自以下的病例匹配肿瘤的广泛基因组图谱相结合： 迄今为止最大的临床注释少数民族患者队列。我们的具体目标将：1） 黑人和西班牙裔患者神经胶质瘤的基因组景观，2）确定种族差异的程度， 在黑人和西班牙裔美国人的组成与疾病定义的分子改变相关，和3）评估 黑人和西班牙裔的生殖系和体细胞变异影响临床结果的程度。我们的工作将 阐明黑人和西班牙裔人群中神经胶质瘤的体细胞和生殖系遗传学，并在此过程中解决 这是该领域的一个重大知识缺口。我们还将建立与祖先相关的 生殖系遗传学，分子特异性胶质瘤亚类，和临床结果，提供了深入了解 神经胶质瘤在不同种族的患者群体中发生和表现的机制。这些发现 应告知治疗开发和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.