Abstract
ctDNA analysis of CSF recapitulates the genomic evolution of brain tumors.
Major finding: ctDNA analysis of CSF recapitulates the genomic evolution of brain tumors.
Approach: ctDNA profiling was performed on CSF samples from patients with low- and high-grade gliomas.
Impact: The ability to perform liquid biopsy using CSF may enhance the diagnosis and treatment of gliomas.
The detection of tumor-associated genomic alterations in circulating tumor DNA (ctDNA) is a highly sensitive and specific alternative to traditional tissue biopsy for the diagnosis, longitudinal monitoring, and precision medicine–guided treatment of cancer. Given the difficulty of performing ctDNA analysis on blood samples in patients with brain tumors, Miller, Shah, Pentsova, and colleagues obtained post-treatment cerebrospinal fluid (CSF) via lumbar punctures from 85 patients with WHO grade IV glioblastoma, WHO grade III glioma, or WHO grade II glioma. The presence of ctDNA was detected by targeted sequencing in CSF from 42 of the 85 patients, which was agnostic of WHO grade, disease duration, or prior therapy and was associated with radiographic tumor progression, tumor burden, and intracranial tumor spread toward the ventricular system and subarachnoid space. Targeted sequencing of matching tumor biopsies and plasma from 36 and 19, respectively, of the 42 patients with ctDNA+ CSF showed that CSF-derived ctDNA mirrored the genomic landscapes observed in the tumor biopsies whereas no ctDNA was found in plasma. This suggests that CSF-derived ctDNA exhibited alterations associated with early gliomagenesis, such as chromosome 1p/19q co-deletion and mutations in IDH1/2 in low-grade gliomas, and clonal mutations. Further, ctDNA from CSF samples obtained from lumbar punctures was highly concordant with ctDNA from CSF obtained contemporaneously from ventricular shunts and gliomas resected within 3 weeks of lumbar puncture–derived CSF collection; moreover, CSF collected near the time of tumor resection more fully recapitulated glioma evolution genomically. Taken together, these results characterize the high genomic concordance between CSF-derived ctDNA and glioma and may be helpful to monitor the evolution of the glioma genome during therapy.
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