J Clin Invest. 2026 Jun 15;136(12):e197391. doi: 10.1172/JCI197391. eCollection 2026 Jun 15.
ABSTRACT
BACKGROUNDLiquid biopsy has emerged as a minimally invasive method for tumor diagnosis, monitoring, and therapeutic guidance. For CNS tumors, cerebrospinal fluid (CSF) provides a reliable and accessible source of tumor-derived cell-free DNA (ctDNA).METHODSThis study evaluates the clinical utility of CSF liquid biopsy in a real-world prospective setting. A total of 148 CSF samples from 120 patients underwent molecular analysis using droplet digital PCR (ddPCR) and/or next-generation sequencing to detect mutations, fusions, copy number alterations, and mismatch-repair deficient signatures (MMRDness). Samples were collected via lumbar puncture (n = 82; 45% ctDNA positive) or from ventricle sources at the time of surgery or through shunts (n = 66; 65% ct DNA positive).RESULTSOverall, ctDNA was detected in 54% of samples with higher detection in high-grade gliomas at diagnosis (100%, 1 sample equivocal) compared with low-grade gliomas (50%). Among low-grade gliomas, ctDNA detection was higher in disseminated cases (80% versus 43%) and from ventricular versus lumbar samples (56% versus 38%).CONCLUSIONLiquid biopsy distinguished relapse from second malignancy and serial sampling demonstrated the potential for ctDNA levels to track treatment response and disease progression. In patients with MMRD tumors, high MMRDness score from ctDNA supported active disease. These findings demonstrate that combined liquid biopsy assays facilitate diagnosis, monitoring, and personalized treatment decisions, offering a viable alternative to invasive surgical biopsies in pediatric CNS tumors.TRIAL REGISTRATIONNone.FUNDINGProof of Principle Grant from The Hospital for Sick Children; The Canadian Institutes of Health Research; The Canadian Cancer Society; The We Love You Connie Foundation; Garron Family Cancer Center at SickKids; SickKids Clinician Training Program; Ben Stelter Foundation through the Women and Children’s Health Research Institute; Jeffrey Brock Cancer Genetics Research Fellowship; Garron Family Cancer Center Research Fellowship/Scotiabank Clinician Scientist Fellowship; Atrium/CMCC and Hold’em for Life Oncology Fellowship; Tokyo Children’s Cancer Study Group Scholarship of the Gold Ribbons Network.
PMID:42294888 | DOI:10.1172/JCI197391
