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.

项目概要 髓母细胞瘤（MB）是儿童最常见的恶性脑肿瘤之一。尽管取得了进展 多模式患者护理和对肿瘤生物学的了解，三分之一的受影响儿童仍然屈服于他们的 疾病。由于缺乏敏感的生物标志物来分层，改善患者治疗效果的努力受到阻碍 治疗反应并预测复发。在复发患者中，治疗过程中潜在的肿瘤演变意味着 可能需要捕获复发时的基因组图谱来确定可行的治疗方法 漏洞。因此，迫切需要新颖、敏感的生物标志物驱动的检测方法来（i）补充 传统的基于成像的疾病评估和（ii）告知复发时的分子目标。液体活检有 最近显示出检测和跟踪肿瘤特异性基因组改变的前景，包括靶向 对从脑肿瘤的脑脊液 (CSF) 中收集的肿瘤来源的游离 DNA (cfDNA) 进行测序 患者。然而，cfDNA 分析对于患有 MB 的儿童的效用仍未得到充分研究。我们最近设计了 以及基于 CSF 衍生的 cfDNA 推断体细胞拷贝数变异 (CNV) 的实验流程 低覆盖率全基因组测序 (lcWGS)。在试点研究中，我们证明了推断全基因组 CNV 的可行性 基于从亚纳克 cfDNA 输入生成的 lcWGS。 70% 的患者检测到肿瘤相关 CNV 基线时获得的 cfDNA 样本中，患有转移性疾病的 MB 患者的可检测性高于患有转移性疾病的 MB 患者 那些没有的。在治疗和随访期间对脑脊液连续 cfDNA 样本的分析表明 CNV 可检测性与病程之间的关联。观察到体细胞 CNV 重新出现 病情进展且可在复发前 3 个月以上的患者通过放射学诊断。此外， 在选定的患者匹配的原发和复发对中观察到不同的 CNV。基于这些发现， 我们假设 CSF 衍生的 cfDNA 中肿瘤特异性体细胞改变的检测将与 扩大的 MB 儿童队列中的患者结局，对其进行纵向分析将增强 了解肿瘤演变和复发的机制。为了检验这些假设，我们建议 (i) 建立 CSF 衍生的 cfDNA 分析的效用，以与疾病负担和预测相关 前瞻性治疗 MB 儿童的衍生队列中的进展情况； (ii) 验证cfDNA的算法 独立 MB 试验队列的分析； (iii) 通过比较研究 MB 中的肿瘤进化 纵向 cfDNA 样本中的体细胞改变。这些研究将在前所未有的队列中进行 从参加两项前瞻性、多机构 MB 试验的儿童中收集的连续 CSF 样本（n=140） 患者; n>600 个 CSF 样本）。拟议的研究预计将建立 CSF 作为最低限度的使用 针对 MB 患者进行侵入性、灵敏且稳健的常规液体活检，具有彻底变革的潜力 对受影响儿童进行风险分层、疾病监测和干预。