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.

项目总结/摘要 尽管手术技术和临床治疗方案取得了进展，但恶性胶质瘤通常在术后进展或复发。 治疗目前，成像数据的视觉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细，无法监测治疗反应或发展预后 亚型成像数据区分1）神经胶质瘤与其他肿瘤（例如，原发性中枢 神经系统淋巴瘤），2）由治疗诱导的假进展（pseudoPD）导致的进展 坏死，或3）最小或残余的肿瘤负荷。最近，我们和其他人发现，神经胶质瘤的潜在驱动因素 疾病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 标记在肿瘤组织中是可识别的;然而，几个研究组已经报道， 使用遗传学和DNA甲基化的特征可以通过非侵入性或微创方法捕获 例如使用诸如血液和脑脊髓液的生物样本的液体活组织检查（LB）。为了解决这个问题， LB在监测胶质瘤进展/复发方面的作用存在差距，我们的目标是建立一种新的检测方法 使用血液来源的无细胞DNA（cfDNA）标记物的DNA甲基化与 最终目标是在真实的时间内对监测和治疗进行微调。利用提取的可用DNA甲基化数据 根据初步诊断时的血清/血浆cfDNA，我们将开发一种非侵入性胶质瘤评分， 与神经胶质瘤的病理相关亚型（例如，G-CIMP-高vs-低），具有独特和 可药物治疗的基因改变（FGFR3-TACC3 [F3-T3]）与胶质瘤的发生 神经纤维瘤病1型（NF 1-胶质瘤）（目的1）。来自跨越纵向样本的可用队列 积累了十多年，我们将描绘成对的原发和复发组的表观基因组（例如，第一， 第二次/或第三次复发），并形成与复发相关的胶质瘤复发（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，好的和差的结果）和复发后作为更具侵袭性的亚型复发的风险 分组。这将评估LB监测术后不同分子进展的准确性。 神经胶质瘤的亚型。我们将利用定量和半定量 常规用于神经胶质瘤诊断和监测的影像学特征， LB神经胶质瘤评分与成熟的神经胶质瘤成像标准，并根据 解决了目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） (Aim 3）。我们的研究将是第一个调查胶质瘤全表观基因组LB标记，以检测侵袭性 胶质瘤在初次诊断和肿瘤进展期间。通过简单的血液检查， 使临床医生能够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获益。