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Background <p>Assessing circulating cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) has been proposed as a promising alternative to tissue biopsy. Advances in cfDNA sequencing have further underscored the potential of CSF liquid biopsies in the clinical setting. CSF is routinely collected for cytologic evaluation at diagnosis and at recurrence in both pediatric and adult central nervous system (CNS) tumors. Preliminary studies have shown that CSF cfDNA analysis may be more sensitive than CSF cytology for detecting the presence of tumor.</p> Methods <p>CSF specimens were prospectively collected from seven pediatric patients with primary CNS malignant tumors. When possible, CSF was collected fresh and from processed cytology specimens. Low-pass whole genome sequencing (LP-WGS) and next-generation sequencing (NGS) using a custom targeted sequencing panel were performed on the specimens to identify copy number alterations (CNAs), detect mutations, and estimate circulating tumor DNA (ctDNA) fractions. Results were compared with matched tumor tissue molecular profiles and corresponding imaging findings.</p> Results <p>Abnormalities in cfDNA were detected in four patients. Sequencing of CSF cytology supernatants demonstrated the presence of circulating tumor DNA with characteristic CNAs and mutations that matched what was seen the tumor tissue as well as the fresh CSF specimens. These studies also revealed tumor heterogeneity and genomic evolution over time.</p> Conclusion <p>This study demonstrates the feasibility of utilizing routinely discarded supernatants from CSF cytology specimens for LP-WGS and targeted NGS. Our approach optimizes the use of CSF that may be limited in pediatric patients as a source for liquid biopsy-based genomic studies. Future research will be necessary to optimize and validate the methodology to enable clinical implementation.</p>

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Cell-free DNA from cerebrospinal fluid cytology specimens as a novel liquid biopsy approach for pediatric patients with primary central nervous system tumors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月5日

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  • Nicholas Chun,
  • Brandon Edelbach,
  • Muhammad Baig,
  • Laura A. T. Kagami,
  • Richard A. Robison,
  • Edwina Choung,
  • Isaac Kremsky,
  • Kevin Leeper,
  • Brian Ferguson,
  • D. Gigi Ostrow,
  • Cindy Fong,
  • Udochukwu Oyoyo,
  • Rajeev Nowrangi,
  • Minwoo Song,
  • Bin Othman,
  • Tanya Minasian,
  • Diem Kieu Tran,
  • Sujata Mushrif,
  • Adina Achiriloaie,
  • Saied Mirshahidi,
  • Gary Yu,
  • Pramil Singh,
  • Ravi Raghavan,
  • Jaclyn A. Biegel,
  • Yan Chen Wongworawat

摘要

Background

Assessing circulating cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) has been proposed as a promising alternative to tissue biopsy. Advances in cfDNA sequencing have further underscored the potential of CSF liquid biopsies in the clinical setting. CSF is routinely collected for cytologic evaluation at diagnosis and at recurrence in both pediatric and adult central nervous system (CNS) tumors. Preliminary studies have shown that CSF cfDNA analysis may be more sensitive than CSF cytology for detecting the presence of tumor.

Methods

CSF specimens were prospectively collected from seven pediatric patients with primary CNS malignant tumors. When possible, CSF was collected fresh and from processed cytology specimens. Low-pass whole genome sequencing (LP-WGS) and next-generation sequencing (NGS) using a custom targeted sequencing panel were performed on the specimens to identify copy number alterations (CNAs), detect mutations, and estimate circulating tumor DNA (ctDNA) fractions. Results were compared with matched tumor tissue molecular profiles and corresponding imaging findings.

Results

Abnormalities in cfDNA were detected in four patients. Sequencing of CSF cytology supernatants demonstrated the presence of circulating tumor DNA with characteristic CNAs and mutations that matched what was seen the tumor tissue as well as the fresh CSF specimens. These studies also revealed tumor heterogeneity and genomic evolution over time.

Conclusion

This study demonstrates the feasibility of utilizing routinely discarded supernatants from CSF cytology specimens for LP-WGS and targeted NGS. Our approach optimizes the use of CSF that may be limited in pediatric patients as a source for liquid biopsy-based genomic studies. Future research will be necessary to optimize and validate the methodology to enable clinical implementation.