By comprehensively integrating genome-scale, loss-of-function genetic screens with RNA sequencing and analysis of DNA methylation patterns, we identified the nuclear serine/threonine kinase vaccinia-related kinase 1 (VRK1) as a highly selective dependency in adult and pediatric CNS and PNS tumors that exhibit low expression of the VRK1 paralog VRK2. This evidence concerns the gene VRK1 and paraneoplastic neurologic syndrome.