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无法治愈的，这表明 需要更好地了解胶质瘤生物学。即使是最近的进展，在功能和临床上 胶质瘤的体细胞遗传学和生殖系遗传学之间的相关关系几乎不存在。在……里面 具体地说，任何或所有胶质瘤风险等位基因在多大程度上推动躯体指定的 胶质瘤的亚型在很大程度上是未知的。这项建议建立在我们与 胶质瘤的胚系特征，并利用现有的散发性胶质瘤患者资料库 来自美国两个最大的癌症中心(MD Anderson(MDA)和Memorial Sloan Ketling(MSK))。 这些资源为我们研究胶质瘤中生殖系和体细胞遗传学的相互作用提供了理想的条件。 进化论。大多数现有的大规模概况分析工作，包括癌症基因组图谱(TCGA)的工作，缺乏 关于疾病治疗和进展的广泛信息以及全基因组生殖系多态性 数据。我们建议对1,350例来自我们医院治疗的2,000多名胶质瘤患者的分子特征进行分析 拥有：1)容易获得的肿瘤组织；2)保存的生殖系DNA；3)详细的临床数据的机构 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 Onco微阵列对这些患者进行密度胚系单核苷酸多态性(SNP)数据 站台。我们现在建议对肿瘤组织进行集中和全面的分子图谱分析 从这位患者队列中确定了胶质瘤亚型和躯体改变模式与 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的易感等位基因 将与不同的躯体改变相关，并预测疾病的演变和结果 在分子上指定的胶质瘤亚类中。我们提出了以下具体目标：目标1。 确定与分子和临床不同相关的生殖系易感等位基因谱 胶质瘤亚类。目的2.通过将生殖系易感等位基因与特异性等位基因相关联来改进风险分层 个别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 从分子发病机制和患者的角度看胶质瘤的概念化 管理层。种系遗传学、分子亚类和体细胞变化之间的密切联系 将提供新的见解，了解不同的肿瘤亚型如何在特定的患者群体中产生，甚至是点 通过确定早期、转化前的序列来制定治疗发展战略 分子事件。此外，这些数据还可以对高危人群进行有针对性的监测和早期发现 人口，这一管理策略对胶质瘤患者仍然探索得很少，因此， 有可能改变范式。

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.