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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（MB）是儿童最常见的恶性脑肿瘤之一。尽管进步多模式的患者护理和对肿瘤生物学的理解，三分之一的受影响儿童仍然屈服于他们疾病。缺乏敏感的生物标志物进行分层的努力阻碍了改善患者结局的努力治疗反应并预测复发。在复发患者中，治疗的潜在肿瘤进化意味着识别可起作用的治疗可能需要捕获复发时捕获基因组轮廓漏洞。因此，迫切需要新颖，敏感的生物标志物驱动的测定法基于成像的常规疾病评估和（ii）在复发时告知分子靶标。液体活检有最近显示的有望检测和跟踪肿瘤特异性基因组改变，包括靶向从脑肿瘤的脑脊液（CSF）收集的肿瘤衍生的无细胞DNA（CFDNA）测序患者。但是，CFDNA分析对MB儿童的实用性仍在研究中。我们最近设计了以及用于CSF衍生的CFDNA中推断体拷贝数变体（CNV）的实验管道在低覆盖WGS（LCWG）上。在试点研究中，我们证明了推断全基因组CNV的可行性基于从子纳学CFDNA输入产生的LCWG。在70％中检测到与肿瘤相关的CNV 在基线时获得的CFDNA样品的可检测性高于转移性疾病患者那些没有。在治疗和随访期间对CSF的连续CFDNA样品的分析表明 CNV可检测性与疾病过程之间的关联。在在射线照相上诊断出在复发前的进展，可识别> 3个月的患者。此外，在选定的患者匹配的原发对和复发对中观察到了不同的CNV。基于这些发现，我们假设检测CSF衍生的CFDNA中肿瘤特异性的体细胞改变将与在扩大的MB儿童队列中，患者的结果和此类纵向分析将增强了解肿瘤进化和复发的机制。为了检验这些假设，我们提出（i）建立CSF衍生的CFDNA分析的实用性，以与疾病负担相关和预测前瞻性治疗儿童MB的衍生队列中的进展；（ii）验证CFDNA的算法在独立的MB试验队列中分析；（iii）通过比较调查MB中肿瘤的演变纵向CFDNA样品的体细胞改变。这些研究将在空前的队列中进行从参加两项前瞻性多机构MB试验的儿童收集的串行CSF样品（n = 140 患者; n> 600 CSF样品）。预计拟议的研究将确定CSF的使用最少 MB患者的常规液体活检的侵入性，敏感和鲁棒形式具有革命性的潜力风险分层，疾病监测和干预措施。