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

基本信息

批准号：
10611422
负责人：
JONINE L. BERNSTEIN
金额：
$ 92.34万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-09 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611422
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 Early identification Epidemiology Event Evolution Genetic Genetic Polymorphism Genetic Predisposition to Disease Genomics Glioblastoma Glioma Goals Heterogeneity Individual Infiltration Infrastructure Institution Interdisciplinary Study 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

项目摘要

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.

抽象的尽管存在相当大的分子异质性，但目前所有弥漫性胶质瘤都是无法治愈的，这表明迫切需要治疗需要提高对神经胶质瘤生物学的了解。即使最近取得了进展，功能和临床神经胶质瘤的体细胞遗传学和种系遗传学之间的相关相关性实际上仍然不存在。在特别是，任何或所有神经胶质瘤风险等位基因驱动体细胞指定的发展的程度神经胶质瘤亚类很大程度上是未知的。该提案建立在我们与神经胶质瘤的种系特征，并利用现有的散发性神经胶质瘤患者存储库来自全国最大的两个癌症中心（MD 安德森 (MDA) 和纪念斯隆凯特琳 (MSK)）。这些资源非常适合我们检查神经胶质瘤中种系遗传学和体细胞遗传学的相互作用进化。大多数现有的大规模分析工作，包括癌症基因组图谱 (TCGA) 的工作，都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。我们建议对在我们中心接受治疗的 2,000 多名神经胶质瘤患者中的 1,350 例进行分子分析。具有以下能力的机构： 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、疾病进展和生存率。重要的是，我们已经获得了高使用 Illumina OncoArray 获取这些患者的密度种系单核苷酸多态性 (SNP) 数据平台。我们现在建议对肿瘤组织进行有针对性和全面的分子分析从该患者队列中确定，神经胶质瘤亚类和体细胞改变模式与种系风险等位基因和临床结果测量。我们的总体假设是神经胶质瘤易感性等位基因将与不同的体细胞改变相关联，并预测疾病的演变和结果并属于分子指定的神经胶质瘤亚类。我们提出以下具体目标：目标 1。确定与分子和临床特征相关的种系易感性等位基因谱神经胶质瘤亚类。目标 2. 通过将种系易感性等位基因与特定风险相关联来完善风险分层个体神经胶质瘤亚类内的体细胞改变。我们的发现应该会带来重大创新从分子发病机制和患者的角度，如何概念化胶质瘤管理。种系遗传学、分子亚类和体细胞改变之间的紧密关联将为了解特定患者群体中不同的肿瘤亚型如何出现提供新的见解，甚至指出通过识别早期、转化前的序列来制定治疗开发策略分子事件。此外，这些数据还可以实现有针对性的监测和早期发现高危人群对于神经胶质瘤患者来说，这一管理策略的探索仍显着不足，因此，有可能改变范式。