Establishing the Genomic Landscape of Human Atypical Meningiomas

项目总结/摘要 最常见的原发性颅内肿瘤，脑膜瘤1，2，也是最常见的 这就是问题所在。由于它们被认为是温和的， 尽管有些脑膜瘤确实是恶性的，即使是良性脑膜瘤的颅内位置也可能 是致命的不幸的是，脑膜瘤对放疗和化疗有抵抗力4， 但II级（非典型）和III级（恶性）肿瘤总是复发，需要多次治疗。 手术伴随着发病率的增加，直到肿瘤变得不可手术。尽管他们 尽管其发病率高且可怕，但我们对其病因学的了解仍处于初级阶段。我们知道 某些风险因素，如神经纤维瘤病基因（NF 2）突变，女性（肿瘤承担）， 激素受体）和暴露于电离辐射，显着增加其发病率5，并大大 在许多癌症综合征中，脑膜瘤的风险增加表明有遗传基础。下一个目标- 世代测序研究已经确定了一些参与良性肿瘤发展的遗传途径， 脑膜瘤，6-8，但这些研究一直很小，往往不能区分肿瘤之间的 不同的等级。事实上，目前尚不清楚这三个等级的肿瘤是否反映了一个单一的疾病过程， 高级别肿瘤是否从一开始就是一种不同的疾病实体，但我假设高- 级脑膜瘤具有使其恶性的特定体细胞突变。我的目标是了解 导致脑膜瘤发生恶性转化的机制和开发潜在的生物标志物 和治疗靶点。我的初步数据，基于全外显子组测序（WES），RNA测序 （RNA-seq）和单核苷酸多态性（SNP）阵列研究14个高级别和16个良性 脑膜瘤样本，支持我们的假设，但需要扩大。然而，我们已经 在ARID 1A中发现了一个引人注目的候选者，它编码了Switch/Sucrose Non- 可发酵的（SWI/SNF）核小体重塑复合物，已被发现作为肿瘤抑制剂， 9 -14.位于染色体1 p上，其缺失长期以来与高级别 对于脑膜瘤，ARID 1A可以提供进展的分子机制15 -18。因此，我建议 检查我们收集的超过100例患者样本-迄今为止最大的脑膜瘤样本收集-以 识别低级别和高级别脑膜瘤的分子特征（目标1）。在目标2中，我将确定 ARID 1A在脑膜瘤恶性进展中的作用。 这项研究将极大地增加我们对高等级遗传病分子遗传学的理解。 脑膜瘤，允许早期识别的情况下，将表现不佳，并奠定了基础， 潜在的靶向疗法来治疗这种毁灭性的痛苦。

PROJECT SUMMARY/ABSTRACT The most common primary intracranial tumors, meningiomas1,2, also happen to be most commonly benign—and therein lies the problem. Because of their perceived benignity, they have been relatively unstudied despite the fact that some are indeed malignant and the intracranial location of even benign meningiomas can be lethal. Unfortunately, meningiomas are resistant to radiation and chemotherapy4, leaving surgery as the primary treatment, but grade II (atypical) and III (malignant) tumors invariably recur, requiring multiple operations accompanied by increasing morbidity until the tumors become inoperable. Yet, despite their prevalence and terrible morbidity, our understanding of their etiology remains rudimentary. We know that certain risk factors, such as mutations in the neurofibromatosis gene (NF2), female sex (the tumors bear hormone receptors), and exposure to ionizing radiation, markedly increase their incidence5, and the greatly increased risk of meningioma in a number of cancer syndromes suggests a genetic basis. Targeted next- generation sequencing studies have identified some genetic pathways involved in the development of benign meningiomas,6-8 but these studies have been small and frequently do not distinguish between tumors of different grades. It is not clear, in fact, whether the three grades of tumors reflect a single disease process or whether high-grade tumors are actually a different disease entity from the outset, but I hypothesize that high- grade meningiomas bear specific somatic mutations that make them malignant. My goal is to understand the mechanisms that cause meningioma to undergo malignant transformation and to develop potential biomarkers and therapeutic targets. My preliminary data, based on whole exome sequencing (WES), RNA sequencing (RNA-seq), and single nucleotide polymorphism (SNP) array studies of 14 high-grade and 16 benign meningioma samples, support our hypothesis but need to be expanded. Nevertheless, we have already identified a compelling candidate in ARID1A, which encodes a core component of the Switch/Sucrose Non- Fermentable (SWI/SNF) nucleosome remodeling complex that has been found to act as a tumor suppressor in various malignancies9-14. Located on chromosome 1p, whose deletion has been long associated with high-grade meningiomas, ARID1A could provide a molecular mechanism for progression15-18. I therefore propose to examine our collection of over 100 patient samples—the largest collection of meningioma samples to date—to identify the molecular signatures of low-grade and high-grade meningiomas (Aim 1). In Aim 2, I will determine the role of ARID1A in malignant progression of meningiomas. The proposed research would vastly increase our understanding of the molecular genetics of high-grade meningiomas, allow for early identification of cases that will behave poorly, and lay the groundwork for potential targeted therapies for this devastating affliction.