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

项目摘要/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，影响大约 1：3000人。患有NF1的患者通常有数十到数百个神经纤维瘤，范围在 生物学和临床行为由良性向恶性转变。大约10%-20%的NF1患者将 发生恶性周围神经鞘瘤(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，还没有办法知道哪些个体，更具体地说，哪些病变 任何一个人都可能以恶毒的方式行事。虽然许多患者都接受了筛查 标准的放射成像技术，如PET/CT，用于检测恶性肿瘤的发展，它们是 受到有关特异性、辐射暴露和成本的问题的困扰。有效地识别在哪些人中 恶性进展在NF1社区具有重要的临床意义。一旦确诊， MPNST的五年存活率低至20%。全切除和根治性手术仍然是唯一 已证实对生存有好处的治疗方式。因此，在转移前检测早期MPNSTs和 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格局。我们之前已经描述了遗传图景 我们将对这两种肿瘤进行比较，以确定这两种肿瘤的独特特征。 我们不仅缺乏有效的MPNST检测策略，而且无法可靠地跟踪疾病 确诊后，许多人的负担会加重。这在一定程度上是因为传统的 CT或MRI等成像手段被良性肿瘤的巨大背景混为一谈 用MPNST改变解剖结构和模糊的细微变化。为了避免这一挑战，我们将 在我们之前发表的工作和关于MPNST的初步数据的基础上证明 恶性肿瘤将游离DNA(CtDNA)排放到血液循环中。CtDNA可与正常区分 由于肿瘤细胞产生的DNA发生突变而产生的游离DNA。我们已经开发出一种 基于数字测序的方法，称为Safe-SeqS，可以检测和量化即使是低水平的ctDNA (低至血浆总DNA的0.01%)。 在目标2和目标3中，我们将利用这种对遗传的理解来开发能够轻松和非 恶性周围神经鞘膜瘤与癌前病变背景的侵袭性鉴别 神经纤维瘤病1(NF1)患者的良性神经纤维瘤。在赠款结束时，我们 将对控制丛状细胞恶性进展的遗传因素有更好的生物学理解 从神经纤维瘤到MPNST，并拥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NF1患者结果的能力。

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.