Characterizing germline and somatic alterations by glioma subtypes and clinical outcome

摘要 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不可治愈的，这表明迫切需要 需要提高对胶质瘤生物学的理解。即使有了最新的进展，功能和临床 胶质瘤中体细胞和生殖系遗传学之间的相关性实际上仍然不存在。在 特别是，任何或所有胶质瘤风险等位基因驱动体细胞指定的胶质瘤发展的程度。 神经胶质瘤亚类在很大程度上是未知的。该提案建立在我们与 神经胶质瘤的生殖细胞特征，并利用现有的散发性神经胶质瘤患者库 来自美国两个最大的癌症中心（MD安德森（MDA）和纪念斯隆凯特琳（MSK））。 这些资源使我们能够理想地研究胶质瘤中生殖系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），缺乏 关于疾病治疗和进展的广泛信息，沿着全基因组生殖系多态性 数据我们建议对来自2,000多名神经胶质瘤患者的1,350例病例进行分子特征分析， 机构：1）容易获得的肿瘤组织; 2）储存的生殖系DNA; 3）详细的临床数据 包括治疗信息、疾病进展和存活率。重要的是，我们已经获得了很高的- 使用Illumina OncoArray的这些患者的密度生殖系单核苷酸多态性（SNP）数据 平台我们现在建议对肿瘤组织进行集中和全面的分子分析 从该患者队列中确定了胶质瘤亚类和体细胞改变模式与 生殖系风险等位基因和临床结果测量。我们的总体假设是胶质瘤易感等位基因 将与不同的躯体改变相关，并预测疾病的演变和结果， 并且在分子上指定的神经胶质瘤亚类内。我们提出以下具体目标：目标1。 确定与分子和临床上不同的 神经胶质瘤亚类。目标二。通过将生殖系易感性等位基因与特异性 个体胶质瘤亚类内的体细胞改变。我们的发现应该会带来重大的创新， 胶质瘤是如何概念化的，从分子发病机制和患者的角度来看， 管理生殖系遗传学、分子亚类和体细胞改变之间的强相关性 将为不同的肿瘤亚型如何在特定的患者人群中出现提供新的见解， 通过识别早期阶段的，前转化序列的治疗发展战略， 分子事件此外，这些数据还可以使有针对性的监测和早期发现处于危险中的人。 人群，一个管理策略，仍然显着不足探索神经胶质瘤患者，因此， 有可能改变我们的思维模式

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.