A systematic review of CSF biomarker discovery in neuro-oncology: A roadmap to standardization and clinical application

Abstract Effective diagnosis, prognostication and management of central nervous system (CNS) malignancies traditionally involves invasive brain biopsy but sampling and molecular profiling of cerebrospinal fluid (CSF) is a safer, rapid and non-invasive alternative that can offer a snapshot of the intracranial milieu. While numerous assays and biomarkers have been analyzed, translational challenges remain, and standardization of protocols is necessary. Here we systematically reviewed 141 studies (Medline, SCOPUS, and Biosis databases; published between January 2000 and September 29th, 2022) that molecularly profiled CSF from adults with brain malignancies including glioma, brain metastasis (BrM), and CNS lymphoma (CNSL). We provide an overview of promising CSF biomarkers, propose CSF reporting guidelines, and discuss the various considerations that go into biomarker discovery, including the influence of blood-brain barrier disruption, type of biomarker (i.e., tumor cell DNA, RNA, protein), cell-of-origin, and site of CSF acquisition (e.g., lumbar, ventricular). We also performed a meta-analysis of proteomic datasets, identifying biomarkers in CNS malignancies and establishing a resource for the research community.