Characterizing germline and somatic alterations by glioma subtypes and clinical outcome

神经胶质瘤亚型和临床结果的种系和体细胞改变特征

• 批准号: 10396633
• 负责人: JONINE L. BERNSTEIN
• 金额: $ 149.88万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-09 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396633
• 关键词: 19q; ATRX gene; Adult; Affect; Astrocytoma; Behavior; Biological; Biology; Biometry; Cancer Center; Chromosome Deletion; Classification; Clinical; Clinical Data; Complex; DNA; Data; Development; Diffuse; Disease; Disease Progression; Early Diagnosis; Epidemiology; Event; Evolution; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genomics; Glioblastoma; Glioma; Goals; Heterogeneity; Individual; Infrastructure; Institution; Interdisciplinary Study; Lead; Malignant - descriptor; Methods; Molecular; Molecular Profiling; Mutation; Outcome; Pathogenesis; Patients; Pattern; Populations at Risk; Positioning Attribute; Primary Brain Neoplasms; Progression-Free Survivals; Recurrence; Research; Resources; Risk; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Somatic Mutation; Survival Analysis; Susceptibility Gene; Technology; The Cancer Genome Atlas; Therapeutic; Tissue Sample; Transcend; Tumor Subtype; Tumor Tissue; Variant; Work; clinical heterogeneity; clinical outcome measures; clinically relevant; cohort; density; exome sequencing; experience; genome wide association study; genome-wide; improved; innovation; insight; member; neuro-oncology; novel; oligodendroglioma; patient population; repository; risk stratification; risk variant; therapeutic development; tumor; virtual

ABSTRACT Despite considerable molecular heterogeneity, all diffuse gliomas are incurable at present, signaling an urgent need for improved understanding of glioma biology. Even with recent advances, functional and clinically relevant correlations between somatic and germline genetics in glioma remain virtually nonexistent. In particular, the extent to which any or all glioma risk alleles drive the development of somatically designated glioma subclasses is largely unknown. This proposal builds on our extensive collaborative experience with the germline characterization of glioma, and leverages an existing repository of sporadic glioma patients accrued from two of the nation's largest cancer centers (MD Anderson (MDA) and Memorial Sloan Kettering (MSK)). These resources ideally position us to examine the interaction of germline and somatic genetics in glioma evolution. Most existing large-scale profiling efforts, including those of the Cancer Genome Atlas (TCGA), lack extensive information on disease treatment and progression along with genome-wide germline polymorphism data. We propose to molecularly profile 1,350 cases from a set of over 2,000 glioma patients treated at our institutions with: 1) readily available tumor tissue; 2) stored germline DNA; and 3) detailed clinical data including treatment information, disease progression, and survival. Importantly, we have already obtained high- density germline single nucleotide polymorphism (SNP) data for these patients using the Illumina OncoArray platform. We now propose to conduct focused and comprehensive molecular profiling on tumor tissue ascertained from this patient cohort to correlate both glioma subclass and patterns of somatic alterations with germline risk alleles and clinical outcome measures. Our overall hypothesis is that glioma susceptibility alleles will correlate with distinct sets of somatic alterations and predict disease evolution and outcomes both between and within molecularly designated glioma subclasses. We propose the following specific aims: Aim 1. Determine the spectrum of germline susceptibility alleles associated with molecularly and clinically distinct glioma subclasses. Aim 2. Refine risk stratification by correlating germline susceptibility alleles with specific somatic alterations within individual glioma subclasses. Our findings should lead to significant innovation in how gliomas are conceptualized, from the perspectives for both molecular pathogenesis and patient management. Robust associations between germline genetics, molecular subclass, and somatic alterations will provide novel insights into how distinct tumor subtypes arise in specific patient populations and even point toward strategies for therapeutic development by identifying early-stage, pre-transformative sequences of molecular events. Moreover, these data could also enable targeted surveillance and early detection in at-risk populations, a management strategy that remains strikingly underexplored for glioma patients and, accordingly, has the potential to be paradigm-shifting.

抽象的 尽管分子异质性很大，但所有弥漫性神经胶质瘤目前都无法治愈，这表明紧急 需要改善对神经胶质瘤生物学的了解。即使最近进步，功能和临床上 胶质瘤中的体细胞和种系遗传学之间的相关相关性实际上不存在。在 特别是，任何或所有神经胶质瘤等位基因都在驱动形式指定的发展的程度 神经胶质瘤亚类在很大程度上未知。这项建议是基于我们与 神经胶质瘤的种系表征，并利用零星神经胶质瘤患者的现有存储库 来自美国两个最大的癌症中心（MD Anderson（MDA）和纪念斯隆·凯特林（MSK））。 这些资源理想地将我们定位为检查胶质瘤中种系和躯体遗传学的相互作用 进化。大多数现有的大规模分析工作，包括癌症基因组地图集（​​TCGA）的工作，缺乏 有关疾病治疗和进展以及全基因组种系多态性的广泛信息 数据。我们建议从我们的2,000多名胶质瘤患者中进行分子剖面1,350例 具有以下机构：1）容易获得的肿瘤组织； 2）储存的种系DNA； 3）详细的临床数据 包括治疗信息，疾病进展和生存。重要的是，我们已经获得了高 这些患者使用Illumina oncoarray的密度生殖单核苷酸多态性（SNP）数据 平台。我们现在建议对肿瘤组织进行集中和全面的分子分析 从该患者队列确定以将神经胶质瘤亚类和体细胞改变模式相关联 种系风险等位基因和临床结果指标。我们的总体假设是胶质瘤易感性等位基因 将与不同的躯体改变相关，并预测疾病的演变和两者之间的结果 并在分子指定的神经胶质瘤亚类中。我们提出以下特定目标：目标1。 确定与分子和临床上不同的种系易感性等位基因的频谱 胶质瘤亚类。目标2。通过将种系易感性等位基因与特定的种系敏感性相关联的风险分层 单个神经胶质瘤亚类中的体细胞改变。我们的发现应该导致重大创新 从分子发病机理和患者的角度来看，神经膜瘤如何概念化 管理。种系遗传学，分子亚类和体细胞改变之间的牢固关联 将提供新的见解，以了解特定患者种群中如何出现独特的肿瘤亚型，甚至点 通过确定早期，转换序列的策略 分子事件。此外，这些数据还可以实现目标监视和早期检测 人群，一种管理策略，对于神经胶质瘤患者而言仍然令人着迷，因此 有可能转移范式。