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While the genomic landscape of low- and high-grade gliomas has been characterized and incorporated into further disease classification, its relationship to disease progression and treatment response remains poorly understood. To address this question, we integrated prospective clinical sequencing of 1,007 primary and recurrent tumors from 924 glioma patients with clinical and treatment phenotypes. Genomic alterations in effectors of cell cycle progression were a biomarker of aggressive disease in 1p19q intact IDH-mutant disease, arising preferentially in enhancing and recurrent tumors. When present at recurrence, the lesions were associated with rapid disease progression. These alterations were also present in all astrocytic tumors that ultimately relapsed with alkylating therapy-associated hypermutation. Analysis of matched pre-treatment and post-progression tumors indicated that cell cycle alterations preceded the emergence of hypermutation. In total, 391 patients (42%) harbored a potentially therapeutically actionable lesion in their tumor of which 73 patients (19%) received a diversity of targeted therapies. Both the type of mutation and its clonality were associated with therapeutic sensitivity in this cohort. For instance, RAF dimer-dependent BRAF hotspot mutations arose predominantly in IDH-wildtype glioblastomas, were subclonal, and affected patients did not respond to MAPK-directed therapy. In contrast, BRAF V600 hotspot mutations arose clonally in histologically distinct gliomas, both low- and high-grade, and responded to MAPK-directed therapy (either RAF, MEK or ERK inhibition). Collectively, these data reveal previously unrecognized genomic determinants of disease progression and treatment response in diverse types of glioma and serve as a rationale for utilizing genomic information in clinical care of patients with glioma. Citation Format: Philip Jonsson, Andrew L. Lin, Shahiba L. Ogilvie, Shweta S. Chavan, Andrew T. McKeown, Natalie M. DiStefano, Marc Rosenblum, Lisa M. DeAngelis, Ingo K. Mellinghoff, Barry S. Taylor. Genomic determinants of progression and response to therapy in prospectively characterized glioma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2621.