Liquid Biopsy for Glioma Using Cell-Free DNA in Cerebrospinal Fluid

Simple Summary Glioma is one of the most common primary central nervous system (CNS) tumors, and its molecular diagnosis is crucial. However, surgical resection or biopsy is risky when the tumor is located deep in the brain or brainstem. Liquid biopsy, particularly targeting cell-free DNA (cfDNA) in cerebrospinal fluid (CSF), is a minimally invasive method, and emerges as a promising alternative, overcoming spatial and temporal heterogeneity in CNS tumors. Unlike extracranial cancers, cfDNA in the blood is scarce in CNS tumors, including glioma, emphasizing the relevance of CSF. Several successful studies have been conducted to detect tumor-specific genetic alterations in cfDNA from CSF using digital PCR and/or next-generation sequencing. This review provides an overview of the current status of CSF-based cfDNA-targeted liquid biopsy for gliomas. It delineates distinctions from liquid biopsies for extracranial cancers, addresses prevailing challenges, and explores future prospects in this field.Abstract Glioma is one of the most common primary central nervous system (CNS) tumors, and its molecular diagnosis is crucial. However, surgical resection or biopsy is risky when the tumor is located deep in the brain or brainstem. In such cases, a minimally invasive approach to liquid biopsy is beneficial. Cell-free DNA (cfDNA), which directly reflects tumor-specific genetic changes, has attracted attention as a target for liquid biopsy, and blood-based cfDNA monitoring has been demonstrated for other extra-cranial cancers. However, it is still challenging to fully detect CNS tumors derived from cfDNA in the blood, including gliomas, because of the unique structure of the blood-brain barrier. Alternatively, cerebrospinal fluid (CSF) is an ideal source of cfDNA and is expected to contribute significantly to the liquid biopsy of gliomas. Several successful studies have been conducted to detect tumor-specific genetic alterations in cfDNA from CSF using digital PCR and/or next-generation sequencing. This review summarizes the current status of CSF-based cfDNA-targeted liquid biopsy for gliomas. It highlights how the approaches differ from liquid biopsies of other extra-cranial cancers and discusses the current issues and prospects.