(PQ 6) Exploiting Frequent Alterations in the PRC2 Complex to Distinguish Benign Neurofibromas from Malignant Peripheral Nerve Sheath Tumors

项目概要/摘要 1型神经纤维瘤病是一种常染色体显性遗传性癌症综合征， 1：3000人。NF 1患者通常携带数十至数百个神经纤维瘤， 从良性到恶性的生物学和临床行为。大约10%-20%的NF 1患者 发生恶性外周神经鞘瘤（MPNST），被认为是由恶性进展引起的 已经存在的神经纤维瘤特别是丛状神经纤维瘤被认为是 很多病人。目前，没有办法知道哪些个体，更具体地说，哪些病变 在任何一个个体中都有可能表现出恶性行为。虽然许多患者接受了 标准的放射学技术，如PET/CT检测恶性肿瘤的发展，他们是 由于特异性、辐射暴露和成本等问题，有效地识别个人， 恶性进展将在NF 1群体中具有显著的临床重要性。一旦确诊， MPNST的五年生存率低至20%。根治性手术的全切除仍然是唯一的 具有经证实的生存益处的模式。因此，在转移之前检测早期MPNST， 传播为患者提供了长期生存的最佳机会。在目标1中，我们将破译 丛状神经纤维瘤的遗传背景我们之前已经描述了 我们将比较两者以确定两种肿瘤类型的独特特征。 我们不仅缺乏有效的MPNST检测策略，我们也无法可靠地跟踪疾病 许多人在确诊后会有负担。这部分是由于传统的 诸如CT或MRI的成像方式被良性肿瘤的巨大背景所混淆， 改变解剖结构并掩盖MPNST的细微变化。为了应对这一挑战，我们将 建立在我们以前发表的工作和MPNST的初步数据的基础上， 恶性肿瘤将无细胞DNA（ctDNA）脱落到循环中。ctDNA可以与正常的 细胞游离DNA中的突变的存在，来源于肿瘤细胞的DNA。我们已经开发出一种 基于数字测序的方法，称为Safe-SeqS，可以检测和定量即使是低水平的ctDNA (as低至血浆中总DNA的0.01%）。 在目标2和3中，我们将利用这种遗传理解来开发工具， 从背景癌前病变中侵入性地区分和识别恶性周围神经鞘瘤 和患有神经纤维瘤病1（NF 1）的个体中的良性神经纤维瘤。在拨款结束时，我们 将有一个更好的生物学理解的遗传因素控制恶性进展丛状 神经纤维瘤与MPNST的关系，并具有可用于诊断和检测MPNST的微创工具。 这有可能立即影响我们改善NF 1患者预后的能力。

PROJECT SUMMARY/ABSTRACT Neurofibromatosis type 1 is an autosomal dominant hereditary cancer syndrome that affects approximately 1:3000 individuals. Patients with NF1 often harbor dozens to hundreds of neurofibromas that range in biological and clinical behavior from benign to malignant. Approximately 10-20% of individuals with NF1 will develop a malignant peripheral nerve sheath tumor (MPNST), thought to arise from the malignant progression of pre-existing neurofibromas. In particular, plexiform neurofibromas are thought to be the precursor lesion for many patients. Currently, there is no way of knowing which individuals and more specifically, which lesions within any one individual are likely to behave in a malignant fashion. While many patients are screened with standard radiographic techniques such as PET/CT to detect the development of malignancies, they are plaqued by issues around specificity, radiation exposure and cost. Effectively identifying individuals in whom malignant progression will arise is of significant clinical importance in the NF1 community. Once diagnosed, MPNST has a five-year survival rate as low as 20%. Total resection with radical surgery remains the only modality with proven survival benefit. Therefore, detecting incipient MPNSTs prior to metastasis and dissemination provides patients with the best opportunity for long-term survival. In Aim 1, we will decipher the genetic landscape of plexiform neurofibromas. We have previously described the genetic landscape of MPNSTs and we will compare the two to identify unique signatures of both tumor types. Not only do we lack effective detection strategies for MPNST, we are also unable to reliably track disease burden in many individuals after the diagnosis has been made. This is in part due to the fact that conventional imaging modalities such as CT or MRI are confounded by the tremendous background of benign tumors that alter the anatomy and obscure subtle changes with the MPNST. In order to obviate this challenge, we will build on work that we have previously published and preliminary data on MPNSTs demonstrating that malignancies shed cell free DNA (ctDNA) into the circulation. The ctDNA can be distinguished from normal cell free DNA by the presence of mutations in the DNA derived from neoplastic cells. We have developed a digital sequencing based approach, coined Safe-SeqS, that can detect and quantify even low levels of ctDNA (as low as 0.01% of total DNA in the plasma). In Aims 2 and 3, we will harness this genetic understanding to develop tools that can readily and non- invasively distinguish and identify malignant peripheral nerve sheath tumors from the background premalignant and benign neurofibromas in individuals with neurofibromatosis 1 (NF1). At the conclusion of the grant, we will have a better biological understanding of the genetic factors controlling malignant progression of plexiform neurofibromas to MPNST and have minimally invasive tools that can be used to diagnose and detect MPNSTs. This has the potential to immediately impact our ability to improve outcomes for individuals with NF1.