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

解读黑人和西班牙裔少数群体胶质瘤的种系和体细胞基因组景观

• 批准号: 10246334
• 负责人: Jason Huse
• 金额: $ 37.81万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246334
• 关键词: 19q; Accounting; Address; Affect; African; African American; Age; Asians; Behavior; Bioinformatics; Biology; Cancer Biology; Case-Control Studies; Clinical; Clinical Data; Collaborations; DNA; Data; Development; Disease; Disease Progression; Ethnic Origin; Ethnic group; European; Exhibits; Formalin; Foundations; Genetic; Genetic Polymorphism; Genomics; Glioblastoma; Glioma; Heterogeneity; Hispanics; Incidence; International; Investigation; Knowledge; Light; Malignant Glioma; Malignant neoplasm of brain; Measures; Methodology; Minority; Minority Groups; Modeling; Molecular; Molecular Epidemiology; Molecular Profiling; Mutation; Outcome; Pathogenesis; Pathogenicity; Patients; Pattern; Performance; Predisposition; Prognosis; Recording of previous events; Research; Resources; Risk; Sampling; Single Nucleotide Polymorphism; Site; Source; Specific qualifier value; Specimen; Stratification; Subgroup; The Cancer Genome Atlas; Tumor Subtype; Underrepresented Minority; Variant; Work; base; clinically relevant; cohort; comparative; design; epidemiologic data; experience; genome wide association study; genomic data; genomic locus; improved; innovation; insight; mutant; neuro-oncology; neuropathology; next generation sequencing; patient population; personalized management; prospective; racial and ethnic; recruit; therapeutic development; treatment optimization; treatment strategy; tumor

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.

摘要：项目 3 最近的基因组分析，包括癌症基因组图谱的分析，极大地阐明了分子生物学 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。目前对体细胞和种系知之甚少 黑人或西班牙裔人群的神经胶质瘤景观。此外，年发病率也存在显着差异 这些少数族裔的神经胶质瘤相对于白人的临床表现强烈表明： 这些群体之间存在基本的和临床相关的遗传差异。与这个猜想一致， 我们最近发现种系单核苷酸多态性（SNP）的模式差异相关 按种族划分的神经胶质瘤发病率较高，白人血统较高的黑人和西班牙裔患神经胶质瘤的比例更高 与水平较低的人相比，其发生胶质瘤的风险更大。我们还确定了一组独特的 SNP，不同于 白人中与神经胶质瘤相关的 SNP，似乎赋予黑人和西班牙裔神经胶质瘤易感性。这些 研究结果表明，一项更大规模的研究仅在黑人中探究了体细胞和种系分子谱 和西班牙裔患者，将弥合关键的知识差距，为更优化、个性化的治疗奠定基础 患者管理。该提案的中心假设是，不同的遗传特征、种系和 黑人和西班牙裔的体细胞影响 IDH 突变型和 IDH 野生型神经胶质瘤的风险和临床预后 亚组。我们将把种系 SNP 数据与来自病例匹配肿瘤的广泛基因组分析相结合 迄今为止规模最大、经过临床注释的少数族裔患者队列。我们的具体目标将 1) 描述 黑人和西班牙裔患者神经胶质瘤的基因组景观，2) 决定种族影响的程度 黑人和西班牙裔的成分与疾病定义的分子改变相关，并且 3) 评估 黑人和西班牙裔种系和体细胞变异对临床结果的影响程度。我们的工作将 澄清黑人和西班牙裔人群神经胶质瘤的体细胞和种系遗传学，并在此过程中解决 该领域的重大知识差距。我们还将在与祖先相关的 种系遗传学、分子特异性神经胶质瘤亚类和临床结果，提供对 神经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 应该既为治疗的发展提供信息，又有助于优化患者管理的设计。