Circulating cell-free DNA methylation as an accurate tool for detection and clinical follow-up of glioma

项目摘要/摘要 尽管手术技术和临床方案都有进步，但恶性胶质瘤通常在术后进展或复发。 治疗。目前，对成像数据的目视检查是监测胶质瘤进展的主要手段；然而， 这种方法可能不够准确或精确，不足以监测治疗反应或不断演变的预后。 子类型。成像数据区分1)胶质瘤和其他肿瘤(例如，初级中枢肿瘤)的能力有限 神经系统淋巴瘤)，2)由治疗引起的假性进展(假性PD) 坏死，或3)微小或残留的肿瘤负担。最近，我们和其他人发现，胶质瘤的潜在驱动因素 进展是由基因突变和表观遗传异常介导的。一般来说，癌症分子 在肿瘤组织中可以识别特征；然而，几个小组报告了肿瘤特异性的 同时使用遗传学和DNA甲基化的签名可以通过非侵入性或微创方法捕获 例如使用血液和脑脊液等生物标本的液体活检术。要解决这一知识 Lb在监测胶质瘤进展/复发中的作用存在差距，我们的目标是建立一种新的方法来检测 恶性胶质瘤术后血源性游离DNA(CfDNA)标志物DNA甲基化的研究 最终目标是实时微调监测和治疗。提取了可用的DNA甲基化数据 根据初始诊断时的血清/血浆cfDNA，我们将开发一种非侵袭性胶质瘤评分，这与 对于预后相关的胶质瘤亚型(例如，G-CIMP-高VS-低)，具有独特和 可药物遗传改变(FGFR3-TACC3[F3-T3])与脑胶质瘤患者的发展 神经纤维瘤病1型(NF1-胶质瘤)(AIM 1)。从横跨纵向样本的现有队列中 积累了十多年，我们将描述成对的初级和递归集合的表观基因组(例如，首先， 第二次/或第三次复发)，并出现胶质瘤复发(GliomaR)-与复发相关的评分，以及 对治疗的反应(目标2)。根据我们定义的评分，我们将患者分类为定义的预后 组(例如，预后好和差)和复发时复发为更具侵袭性的亚型的风险 子组。这将评估LB监测不同分子术后进展的准确性 贯穿个体疾病的神经胶质瘤的亚型。我们将利用定量和半定量 常规用于脑胶质瘤诊断和监测的影像特征与表观基因组标记的相关性 根据建立良好的胶质瘤成像标准对LB-Glioma-Score进行调整 解决目前人脑胶质瘤影像资料的局限性(如假性PD和放射性坏死) (目标3)。我们的研究将是第一次研究胶质瘤全表观基因组LB标记以检测侵袭性 初诊时和肿瘤进展过程中的胶质瘤。通过简单的血液测试就能做出准确的诊断 允许临床医生实时检测疾病的演变，从而识别可能 在干预可能更有效的早期阶段从更积极的治疗中受益。

PROJECT SUMMARY/ABSTRACT Despite advances in surgical techniques and clinical regimens, malignant gliomas usually progress or recur after treatment. Currently, visual inspection of imaging data is the mainstay to monitor glioma progression; however, this approach may not be accurate or refined enough to monitor treatment response or evolving prognostic subtypes. Imaging data has limited ability to distinguish 1) gliomas from other tumors (e.g., primary central nervous system lymphoma), 2) progression from pseudoprogression (pseudoPD) resulting from therapy-induced necrosis, or 3) minimal or remnant tumoral burden. Recently, we and others found that potential drivers of glioma progression are mediated by gene mutation and epigenetic abnormalities. Generally, cancer molecular signatures are identifiable in tumoral tissue; however, several groups have reported that tumor specific signatures using both genetics and DNA methylation can be captured by non- or minimally-invasive approach such as liquid biopsy (LB) using biospecimens such as blood and cerebrospinal fluid. To address this knowledge gap in the role of LB to monitor glioma progression/recurrence, we aim to establish a novel approach to detect postoperative malignant glioma using DNA methylation of blood-derived cell-free DNA (cfDNA) markers with the ultimate goal to fine-tune surveillance and treatment in real time. With available DNA methylation data extracted from serum/plasma cfDNA at initial diagnosis, we will develop a non-invasive Glioma-score that is associated with prognostically relevant subtypes of glioma (e.g., G-CIMP-high vs -low), gliomas harboring unique and druggable genetic alterations (FGFR3-TACC3 [F3-T3]) and gliomas developing in patients with Neurofibromatosis type 1 (NF1-glioma) (Aim 1). From available cohorts spanning longitudinal specimens accrued for more than a decade, we will profile the epigenome of paired primary and recurrent sets (e.g., first, second /or third recurrence), and develop a Glioma recurrence (GliomaR)-score associated with recurrence, and response to therapy (Aim 2). Based on our defined scores, we will classify patients into defined prognostic groups (e.g., good and poor outcome) and risk to recur as a more aggressive subtype upon recurrence subgroups. This will assess the accuracy of LB to monitor postoperative progression of different molecular subtypes of glioma throughout an individual’s disease. We will utilize the quantitative and semi-quantitative imaging features routinely used in the diagnosis and monitoring of glioma to correlate the epigenomic markers of the LB Glioma-score with well established glioma imaging standards and tailor the LB score towards the resolution of the current limitations of imaging data for human glioma (e.g., pseudoPD and radiation necrosis) (Aim 3). Our study will be the first to investigate glioma whole-epigenome LB markers to detect aggressive gliomas at initial diagnosis and during tumor progression. Accurate diagnosis through a simple blood test will allow clinicians to detect the evolution of the disease in real-time, thus identifying high-risk patients who may benefit from more aggressive therapy at an earlier point when intervention could be more effective.