What question did this study set out to answer?

This research aims to assess the effectiveness of cerebrospinal fluid circulating tumor DNA as a marker for measurable residual disease in CNS germ cell tumors.

June 26, 2026Open Access

ID #717 Cerebrospinal fluid circulating tumor DNA as marker of measurable residual disease for CNS germ cell tumors – an international pediatric brain tumor liquid biopsy collaborative

Key Points

This research aims to assess the effectiveness of cerebrospinal fluid circulating tumor DNA as a marker for measurable residual disease in CNS germ cell tumors.
Multi-institutional cohort study of CNS-GCT patients treated with induction chemotherapy and radiation.
CSF collected at diagnosis, during therapy, and post-treatment for ctDNA analysis using whole-genome sequencing.
Patient outcomes monitored for ctDNA persistence and recurrence post-induction therapy.
ctDNA was detected in 95% of germinoma and 88% of NGGCT patients at diagnosis, including those with negative tumor markers.
Persistent ctDNA was noted in 27% of samples after chemotherapy cycles and in 25% post-induction therapy, indicating higher risk of recurrence.
Genetic profiling revealed resistant clones at relapse, highlighting the importance of ctDNA monitoring.

Abstract

Abstract Background Liquid biopsy enables profiling of CNS tumors without surgery and tracking minimal residual disease. Our pilot work indicated high detection rate of circulating tumor DNA (ctDNA) from CSF of patients with CNS germ cell tumors (CNS-GCT) at diagnosis. Herein, we present an expanded, international dataset with longitudinal sampling to evaluate the dynamics of CSF-ctDNA. Methods A multi-institutional cohort of CNS-GCT patients treated with induction chemotherapy and response-adapted radiation was assembled. CSF was collected at diagnosis, during therapy, and after completion of treatment. Cell-free DNA was extracted for studying copy-number variations (CNVs) using low-pass whole-genome sequencing, with additional mutational analysis by panel sequencing when available. ctDNA positivity is inferred by the presence of CNVs +/- mutations. Results One-hundred and fifty-eight samples from 77 patients (median age 13 years; germinoma=48, NGGCT=29) were analyzed. At diagnosis, ctDNA was detected in 95% (37/39) of germinoma, and 88% (15/17) of NGGCT patients, including all patients with negative tumor markers (n = 21). Where mutational analysis was performed (n = 27), oncogenic drivers in the form of amplifications or mutations were identified in 96% (26/27). Longitudinal CSF profiling revealed persistent ctDNA in 27% of samples (6/22) after 1-2 cycles of chemotherapy, and in 25% (6/24) after induction therapy, prior to irradiation. Among patients with persistent ctDNA post-induction, three developed early recurrence despite negative ctDNA following radiation, and one demonstrated refractory disease, representing only events to-date. Evolution of CNV profiles was observed from paired-CSF at diagnosis and relapse, suggesting emergence of resistant clones. Conclusion Liquid biopsy enables the minimally invasive diagnosis and genotyping of CNS-GCTs. Early clearance of ctDNA was observed in the majority, while persistence following induction therapy may serve as a poor prognostic marker. Evidence based on the largest entity-specific CSF cohort supports the prospective incorporation of serial CSF liquid biopsies for personalized, response-adapted, management of CNS-GCTs.

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