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.

项目概要/摘要 尽管手术技术和临床治疗方案取得了进步，但恶性胶质瘤通常在手术后进展或复发。 目前，影像数据的目视检查是监测神经胶质瘤进展的主要手段； 这种方法可能不够准确或不够完善，无法监测治疗反应或不断变化的预后 影像学数据区分 1) 神经胶质瘤和其他肿瘤（例如原发性中枢性肿瘤）的能力有限。 神经系统淋巴瘤），2）治疗引起的假性进展 (pseudoPD) 的进展 坏死，或3）最小或残余肿瘤负荷最近，我们和其他人发现神经胶质瘤的潜在驱动因素。 通常是由基因突变和表观遗传异常介导的。 肿瘤组织中的特征是可识别的；然而，一些研究小组报告说，肿瘤特异性 可以通过非侵入性或微创方法捕获使用遗传学和 DNA 甲基化的特征 例如使用血液和脑脊液等生物样本进行液体活检 (LB) 来解决这一问题。 由于 LB 在监测神经胶质瘤进展/复发方面的作用存在差距，我们的目标是建立一种新的方法来检测 使用血源性游离 DNA (cfDNA) 标记物的 DNA 甲基化进行术后恶性神经胶质瘤 最终目标是利用提取的可用 DNA 甲基化数据实时微调监测和治疗。 根据初步诊断时的血清/血浆 cfDNA，我们将开发一个与 与预后相关的神经胶质瘤亚型（例如，G-CIMP-高与-低），神经胶质瘤具有独特的和 可药物基因改变（FGFR3-TACC3 [F3-T3]）和患有以下疾病的患者中发生的神经胶质瘤 1 型神经纤维瘤病（NF1-神经胶质瘤）（目标 1）。 经过十多年的积累，我们将分析配对的初级组和循环组的表观基因组（例如，第一组、 第二次/或第三次复发），并制定与复发相关的神经胶质瘤复发 (GliomaR) 评分，以及 对治疗的反应（目标 2）根据我们定义的评分，我们将患者分为定义的预后。 组（例如，良好和不良结果）以及复发后作为更具侵袭性亚型复发的风险 这将评估 LB 监测不同分子术后进展的准确性。 我们将利用定量和半定量方法来分析个体疾病中的神经胶质瘤亚型。 常规用于神经胶质瘤诊断和监测的成像特征，以关联表观基因组标记 具有完善的神经胶质瘤成像标准的 LB 神经胶质瘤评分，并根据 解决当前人类神经胶质瘤成像数据的局限性（例如，假性PD和放射性坏死） （目标 3）我们的研究将是第一个研究胶质瘤全表观基因组 LB 标记以检测侵袭性的研究。 通过简单的血液测试即可在初始诊断和肿瘤进展过程中准确诊断神经胶质瘤。 允许实时检测疾病的演变，从而识别可能的高危患者 尽早从更积极的治疗中受益，此时干预可能会更有效。