# Cerebrospinal fluid derived circulating tumor DNA as a clinically relevant biomarker in medulloblastoma

> **NIH NIH R21** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $209,791

## Abstract

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 liq...

## Key facts

- **NIH application ID:** 10112647
- **Project number:** 1R21CA256386-01
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Paul Northcott
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $209,791
- **Award type:** 1
- **Project period:** 2021-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112647

## Citation

> US National Institutes of Health, RePORTER application 10112647, Cerebrospinal fluid derived circulating tumor DNA as a clinically relevant biomarker in medulloblastoma (1R21CA256386-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10112647. Licensed CC0.

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