Objective: High-grade glioma (HGG) rarely spreads outside the CNS. To test the hypothesis that the lesions were metastases originating from an HGG, we sequenced the relapsing HGG and distant extraneural lesions. Methods: We performed whole-exome sequencing of an HGG lesion, its local relapse, and distant lesions in bone and lymph nodes. Results: Phylogenetic reconstruction and histopathologic analysis confirmed the common glioma origin of the secondary lesions. The mutational profile revealed an IDH1/2 wild-type HGG with an activating mutation in EGFR and biallelic focal loss of CDKN2A (9p21). In the metastatic samples and the local relapse, we found an activating PIK3CA mutation, further copy number gains in chromosome 7 (EGFR), and a putative pathogenic driver mutation in a canonical splice site of FLNA. Conclusions: Our findings demonstrate tumor spread outside the CNS and identify potential genetic drivers of metastatic dissemination outside the CNS, which could be leveraged as therapeutic targets or potential biomarkers.