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Updated: Oct 29, 2025
Detection and Monitoring of Tumor Associated Circulating DNA in Patient Biofluids
Published on: June 8, 2019
Tumor DNA Mutations From Intraparenchymal Brain Metastases Are Detectable in CSF
Stephanie Kim Cheok1, Azeet Narayan2, Anna Arnal-Estape3,4
1Department of Neurosurgery, Yale University, New Haven, CT.
Abstract:
Discordant responses between brain metastases and extracranial tumors can arise from branched tumor evolution, underscoring the importance of profiling mutations to optimize therapy. However, the morbidity of brain biopsies limits their use. We investigated whether cell-free DNA (cfDNA) in CSF could serve as an effective surrogate marker for genomic profiling of intraparenchymal (IP) brain metastases.
Methods:
CSF and blood were collected simultaneously from patients with progressive brain metastases undergoing a craniotomy or lumbar puncture. Mutations in both biofluids were measured using an error-suppressed deep sequencing method previously published by our group. Forty-three regions of 24 cancer-associated genes were assayed.
Results:
This study enrolled 14 patients with either IP brain metastases (n = 12) or cytology-positive leptomeningeal disease (LMD, n = 2) and two controls with normal pressure hydrocephalus. Primary cancer types were lung, melanoma, renal cell, and colorectal. cfDNA was measurable in all sixteen samples of CSF. Cancer-associated mutations were found in the CSF of ten patients (eight with IP [67%] and two with LMD [100%]) and plasma of five patients (five with IP [42%] and none with LMD). All patients with plasma cfDNA had extracranial tumors. Among the five patients in the cohort who also had mutation data from time-matched brain metastasis tissue, four patients (80%) had matching mutations detected in CSF and brain, whereas only one patient (20%) had matching mutations detected in plasma and brain.
Conclusion:
The detection of mutational DNA in CSF is not restricted to LMD and was found in two thirds of patients with IP brain metastases in our cohort. Analysis of CSF can be a viable alternative to biopsy for detection of somatic mutations in brain metastases.
Insights
Cerebrospinal fluid (CSF) cell-free DNA (cfDNA) analysis can detect brain tumor mutations, offering a less invasive alternative to biopsies for intraparenchymal brain metastases.
Area of Science:
- Neuro-oncology
- Cancer Genomics
- Liquid Biopsy
Background:
- Discordant tumor responses between brain and extracranial sites necessitate mutation profiling for optimal therapy.
- Brain biopsies are invasive and carry significant morbidity, limiting their clinical utility.
- Cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) is explored as a non-invasive surrogate for genomic analysis of brain metastases.
Purpose of the Study:
- To evaluate the efficacy of CSF cfDNA as a surrogate marker for genomic profiling of intraparenchymal (IP) brain metastases.
- To compare cfDNA mutation detection in CSF and plasma against matched brain tissue.
Main Methods:
- Simultaneous collection of CSF and blood from patients with progressive brain metastases.
- Deep sequencing of 43 cancer-associated genes in cfDNA from CSF and plasma.
- Comparison of cfDNA mutation data with matched brain metastasis tissue.
Main Results:
- cfDNA was detectable in all CSF samples.
- Cancer-associated mutations were identified in CSF from 67% of IP brain metastases patients and 100% of leptomeningeal disease (LMD) patients.
- CSF cfDNA mutation profiles showed higher concordance (80%) with brain tissue than plasma cfDNA (20%).
Conclusions:
- CSF cfDNA analysis is a viable alternative to biopsy for detecting somatic mutations in brain metastases.
- Mutation detection in CSF is feasible even in intraparenchymal lesions, not just LMD.
- CSF cfDNA offers a promising non-invasive approach for guiding targeted therapies in brain metastases.
