We are developing an innovative, minimally invasive method to study the genetic spectrum of tumors metastatic and primary to the central nervous system (CNS). Cell free DNA (cfDNA) acts as a tumor fingerprint, allowing detection of genetic alterations that mark the variation and progression of disease. As a clinical tool, it may supplant the currently available and relatively insensitive methods of brain tumor diagnosis. As a scientific tool, novel tumor cfDNA mutations identified in CSF will allow for great insight into tumor biology, and more faithful animal modeling of these diseases. Specific Aim 1: Develop novel microfluidic chips to isolate and characterize cfDNA within the CSF of patients with primary and metastatic brain tumors. Specific Aim 2: Refine new sequencing techniques to characterize tumor cfDNA in CSF from patients with CNS tumors. Determine the feasibility of supplanting cytology with tumor cfDNA sequencing in the diagnosis of leptomeningeal metastasis. Specific Aim 3: Subtype primary brain tumors through the development of single-gene copy number variation sequencing of cfDNA in CSF. Summary: cfDNA in CSF from brain tumors shows great promise to track cancer's mutation profile, diagnose disease, and inform treatment. The techniques accelerated here may revolutionize the recognition of leptomeningeal metastases, and deepen our scientific understanding of brain tumor progression.