Cerebrospinal fluid derived circulating tumor DNA as a clinically relevant biomarker in medulloblastoma

脑脊液来源的循环肿瘤 DNA 作为髓母细胞瘤的临床相关生物标志物

• 批准号: 10323055
• 负责人: Paul Northcott
• 金额: $ 24.67万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323055
• 关键词: Adult; Affect; Algorithms; Biological Assay; Biological Markers; Blinded; Body Fluids; Brain Neoplasms; Cell Extracts; Central Nervous System Neoplasms; Cerebrospinal Fluid; Child; Child Care; Childhood Brain Neoplasm; Clinic; Clinical; Clinical Trials; Collection; Complement; Copy Number Polymorphism; DNA Sequence Alteration; DNA analysis; Data; Derivation procedure; Detection; Diagnosis; Disease; Disease Progression; Early Diagnosis; Enrollment; Evaluation; Event; Evolution; Gene Mutation; Genetic; Genetic Fingerprintings; Genomics; Glioma; Goals; Heterogeneity; Image; Infratentorial Neoplasms; Intervention; Leptomeninges; Malignant Childhood Central Nervous System Neoplasm; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of brain; Microscopic; Molecular; Molecular Target; Monitor; Neoplasm Metastasis; Patient Care; Patient-Focused Outcomes; Patients; Pattern; Pediatric Neoplasm; Pilot Projects; Prospective cohort; Recurrence; Recurrent disease; Relapse; Reporting; Research; Residual Tumors; Saint Jude Children' s Research Hospital; Sampling; Series; Solid Neoplasm; Source; Surrogate Markers; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Sample; Tumor Biology; Tumor Burden; Tumor-Derived; Validation; base; biomarker-driven; burden of illness; cell free DNA; clinically relevant; cohort; conventional therapy; follow-up; genome sequencing; genome-wide; genomic data; genomic profiles; improved; insight; liquid biopsy; medulloblastoma; minimally invasive; mortality; multimodality; neuroimaging; novel; prospective; radiological imaging; relapse patients; relapse prediction; response; risk stratification; standard of care; targeted sequencing; treatment response; tumor; tumor DNA; tumor progression; whole genome

PROJECT SUMMARY Medulloblastoma (MB) is among the most common malignant brain tumors in children. Despite advances in multi-modal patient care and understanding of tumor biology, one-third of affected children still succumb to their disease. Efforts to improve patient outcome have been hindered by the lack of sensitive biomarkers to stratify treatment response and predict relapse. In relapsing patients, potential tumor evolution with treatment implies that capturing genomic profiles at recurrence might be required for identifying actionable therapeutic vulnerabilities. There is thus a dire need for novel, sensitive biomarker-driven assays to (i) complement conventional imaging-based disease evaluation and (ii) inform molecular targets at relapse. Liquid biopsies have recently shown promise for detecting and tracking tumor-specific genomic alterations, including targeted sequencing of tumor-derived cell-free DNA (cfDNA) collected from the cerebrospinal fluid (CSF) of brain tumor patients. However, the utility of cfDNA analysis for children with MB remains understudied. We recently devised and an experimental pipeline for inferring somatic copy number variants (CNVs) in CSF-derived cfDNA based on low-coverage WGS (lcWGS). In pilot studies, we demonstrated feasibility of inferring genome-wide CNVs based on lcWGS generated from sub-nanogram cfDNA inputs. Tumor-associated CNVs were detected in 70% of cfDNA samples obtained at baseline, with higher detectability in MB patients with metastatic disease than in those without. Analysis of serial cfDNA samples from CSF during treatment and follow-up indicated an association between CNV detectability and disease course. Re-emergence of somatic CNVs was observed in patients who progressed, identifiable >3 months before relapse was diagnosed radiographically. In addition, divergent CNVs were observed in selected patient-matched primary and relapse pairs. Based on these findings, we hypothesize that the detection of tumor-specific somatic alterations in CSF-derived cfDNA will correlate with patient outcomes in an expanded cohort of children with MB, and longitudinal profiling of such will enhance understanding of mechanisms underlying tumor evolution and recurrence. To test these hypotheses, we propose to (i) establish the utility of CSF-derived cfDNA profiling for correlation with disease burden and prediction of progression in a derivation cohort of prospectively treated children with MB; (ii) validate the algorithm of cfDNA analysis in an independent MB trial cohort; and (iii) investigate tumor evolution in MB through comparison of somatic alterations in longitudinal cfDNA samples. These studies will be conducted in an unprecedented cohort of serial CSF samples collected from children enrolled on two prospective, multi-institutional MB trials (n=140 patients; n>600 CSF samples). The proposed research is anticipated to establish the use of CSF as a minimally invasive, sensitive, and robust form of routine liquid biopsy for MB patients with the potential of revolutionizing risk stratification, disease monitoring, and intervention for affected children.

项目摘要 髓母细胞瘤是儿童最常见的恶性脑肿瘤之一。尽管取得了进展， 尽管有多模式的病人护理和对肿瘤生物学的了解，三分之一的受影响儿童仍然死于他们的癌症。 疾病由于缺乏敏感的生物标志物进行分层， 治疗反应和预测复发。在复发患者中，治疗后潜在的肿瘤演变意味着 在复发时捕获基因组谱可能是鉴定可操作的治疗方法所必需的， 漏洞因此，迫切需要新的、灵敏的生物标志物驱动的测定来（i）补充 常规的基于成像的疾病评估和（ii）在复发时告知分子靶点。液体活检 最近显示出用于检测和跟踪肿瘤特异性基因组改变的前景，包括靶向的 从脑肿瘤的脑脊液（CSF）收集的肿瘤来源的无细胞DNA（cfDNA）的测序 患者然而，cfDNA分析对MB儿童的效用仍未得到充分研究。我们最近设计了 以及用于推断CSF衍生的cfDNA中的体细胞拷贝数变体（CNV）的实验管道， 低覆盖率WGS（lcWGS）。在初步研究中，我们证明了推断全基因组CNVs的可行性， 基于从亚纳克cfDNA输入产生的IcWGS。肿瘤相关的CNVs在70%的患者中检出 在基线时获得的cfDNA样本中，具有转移性疾病的MB患者的可检测性高于具有转移性疾病的MB患者的可检测性。 那些没有。治疗和随访期间来自CSF的系列cfDNA样品的分析表明， CNV可检测性与病程的相关性。体细胞CNVs的重新出现， 在复发前>3个月可识别的进展患者通过放射学诊断。此外，本发明还提供了一种方法， 在选定的患者匹配的原发和复发配对中观察到不同的CNV。根据这些发现， 我们假设在CSF来源的cfDNA中检测到肿瘤特异性体细胞改变将与 扩大MB儿童队列的患者结局，以及此类纵向分析将增强 了解肿瘤演变和复发的机制。为了验证这些假设，我们建议 （i）建立CSF来源的cfDNA谱分析用于与疾病负担相关和预测 前瞻性治疗MB儿童的衍生队列中的进展;（ii）验证cfDNA算法 在独立的MB试验队列中进行分析;和（iii）通过比较 纵向cfDNA样品中的体细胞改变。这些研究将在前所未有的队列中进行 从两项前瞻性、多机构MB试验（n=140）入组的儿童中采集的连续CSF样本 患者; n>600个CSF样品）。拟议的研究预计将确定CSF的使用作为最低限度的 MB患者常规液体活检的侵入性，敏感性和稳健性，具有革命性的潜力 风险分层、疾病监测和对受影响儿童的干预。