Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging, and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients declines with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma.

近三分之一患有髓母细胞瘤（一种小脑恶性胚胎肿瘤）的儿童死于这种疾病。通过成像和脑脊液 (CSF) 细胞学进行的传统反应监测仍然具有挑战性，并且缺乏可测量残留病 (MRD) 的标志物。在这里，我们展示了脑脊液衍生的游离 DNA (cfDNA) 作为 MRD 生物标志物的临床实用性，该生物标志物从参加前瞻性试验的髓母细胞瘤儿童（123 名患者，476 个样本）收集的系列样本中获得。使用低覆盖率全基因组测序，将脑脊液衍生的 cfDNA 中与肿瘤相关的拷贝数变异作为 MRD 替代物进行研究。在基线时，85% 和 54% 的转移性和局限性疾病患者中分别检测到 MRD。随着治疗的进行，MRD 阳性患者的数量有所减少，但那些持续存在 MRD 的患者的进展风险明显更高。重要的是，在一半的复发患者中，MRD 检测先于放射学进展。我们的研究结果主张在未来的髓母细胞瘤试验中对脑脊液来源的液体活检进行前瞻性评估。