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

循环游离 DNA 甲基化作为神经胶质瘤检测和临床随访的准确工具

• 批准号: 10660090
• 负责人: Houtan Noushmehr
• 金额: $ 58.35万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-10 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660090
• 关键词: Address; Aftercare; Biopsy; Blood; Blood Tests; Brain Neoplasms; Central Nervous System Lymphoma; Cerebrospinal Fluid; Chromosome Deletion; Classification; Clinical; Clinical Management; Clinical Trials; Complement; Coupled; CpG Island Methylator Phenotype; DNA; DNA Markers; DNA Methylation; Data; Detection; Diagnosis; Disease; Disease Progression; Epigenetic Process; Evaluation; Evolution; Excision; FGFR3 gene; Freezing; Gene Mutation; Genetic; Genomics; Glioblastoma; Glioma; Goals; Histology; Human; Image; Individual; Inflammatory; Interdisciplinary Study; Intervention; Intracranial Neoplasms; Knowledge; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Mediating; Molecular; Molecular Analysis; Molecular Evolution; Molecular Target; Monitor; Monitoring for Recurrence; Mutation; NF1 gene; NF1 mutation; Necrosis Induction; Neoplasm Circulating Cells; Neurofibromatosis 1; Operative Surgical Procedures; Outcome; Patients; Pattern; Phenotype; Plasma; Plasma Cells; Postoperative Period; Procedures; Prospective cohort; Protocols documentation; Publishing; Radiation necrosis; Records; Recurrence; Recurrence Score; Regimen; Reporting; Resolution; Risk; Role; Serum; Somatic Mutation; Specimen; Subgroup; System; TACC3 gene; Techniques; Testing; Time; Tissues; Tumor Biology; Tumor Burden; Tumor Tissue; Variant; Visual; Work; accurate diagnosis; aggressive therapy; biomarker identification; cell free DNA; chromatin modification; clinically relevant; cohort; contrast enhanced; diagnostic biomarker; disease diagnosis; epigenetic marker; epigenome; epigenomics; follow-up; high risk; human data; imaging biomarker; improved; insight; liquid biopsy; metabolic imaging; methylome; minimally invasive; molecular dynamics; molecular subtypes; novel strategies; patient stratification; perfusion imaging; prognostic; prognostic assays; prospective; quantitative imaging; serial imaging; standard of care; tool; treatment response; tumor; tumor DNA; tumor molecular fingerprint; tumor progression

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.

项目摘要/摘要 尽管手术技术和临床方案取得了进步，但恶性神经胶质瘤通常会在 治疗。当前，对成像数据的目视检查是监测神经胶质瘤进展的主要中流tay。然而， 这种方法可能不准确或不足以监视治疗响应或不断发展的迅速 亚型。成像数据的区分能力有限1）神经胶质瘤与其他肿瘤（例如，主要中心 神经系统淋巴瘤），2）由治疗诱导的伪雌性进展 坏死，或3）最小或残留的肿瘤伯恩。最近，我们和其他人发现神经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。通常，癌症分子 特征在肿瘤组织中可识别；但是，有几个小组报告说肿瘤特异性 使用遗传学和DNA甲基化的签名可以通过非或微创方法捕获 例如使用血液和脑脊液等生物测量的液体活检（LB）。解决这一知识 LB在监测神经胶质瘤进展/复发中的作用差距，我们旨在建立一种新的方法来检测 术后恶性神经胶质瘤使用血液来源的无细胞DNA（CFDNA）标记的DNA甲基化 实时微调监视和治疗的最终目标。提取了可用的DNA甲基化数据 从最初诊断性的血清/血浆CFDNA从血清/血浆CFDNA中 具有胶质瘤的预测相关亚型（例如，G-CIMP-High vs-Low），具有独特和 可药物遗传改变（FGFR3-TACC3 [F3-T3]）和神经胶质瘤患者 1型神经纤维瘤病（NF1-胶质瘤）（AIM 1）。从可用的纵向标本的可用队列中 在十多年中，我们将介绍配对的主要和复发集的表观基因组（例如，首先， 第二 /或第三复发），并形成与复发相关的神经胶质瘤复发（神经胶质瘤）的评分 对治疗的反应（AIM 2）。基于我们定义的分数，我们将将患者分类为定义的预后 小组（例如，良好和差的结果）和复发后重复出现的风险，复发后更具侵略性的亚型 亚组。这将评估LB监测不同分子术后进展的准确性 整个个体疾病中神经胶质瘤的亚型。我们将利用定量和半定量 通常用于诊断和监测神经胶质瘤的成像特征，以使表观基因组标记相关 LB神经瘤评分具有良好的神经胶质瘤成像标准，并根据LB评分量 人神经胶质瘤成像数据的当前局限性的分辨率（例如，伪和辐射坏死） （目标3）。我们的研究将是第一个研究胶质瘤全异象组LB标记以检测侵略性的研究 初始诊断和肿瘤进展过程中的神经胶质瘤。通过简单的血液检查准确的诊断将 允许临床医生实时检测疾病的演变，从而确定可能 在干预更有效的早期时，从更具积极的治疗中受益。