Abstract Extrachromosomal DNA (ecDNA) is a key driver of oncogene amplification, treatment resistance, and poor survival outcomes in human cancer, including medulloblastoma. To date, ecDNA detection has largely relied on whole-genome sequencing of tumor DNA isolated from surgical resections. Here, we describe the feasibility of minimally invasive ecDNA detection and reconstruction in cerebrospinal fluid (CSF) liquid biopsies when applied to both low-coverage whole-genome sequencing and enzymatic methyl-sequencing data obtained from 679 CSF samples across 220 medulloblastoma patients. Recurrent ecDNAs involving canonical medulloblastoma driver loci, including MYC, PVT1, MYCN, GLI2, and CCND2, were detected in the CSF of 26/220 (12%) patients across the cohort, consistent with frequencies reported in prior medulloblastoma tumor tissue studies. Presence of ecDNA in the CSF was associated with significantly worse progression-free survival compared with patients lacking amplification signals. Reconstructed ecDNA segments from patients with longitudinal sampling demonstrated structural conservation across treatment and clinical progression. Our computational framework applied to CSF liquid biopsies offers a minimally invasive approach for ecDNA detection, molecular characterization, and monitoring in pediatric neuro-oncology settings that is anticipated to be broadly applicable.
Tian et al. (Tue,) studied this question.