Early distant progression in adult Histone-3 K27-altered diffuse midline gliomas

PURPOSE: H3 K27-altered diffuse midline glioma (DMG) is a molecularly defined, highly aggressive tumor entity since the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). It has been most extensively characterized in children and adolescents and continues to pose significant challenges to treating physicians due to its growth along the midline structures of the brain and its ability to progress distantly leading to poor prognosis. Clinical and molecular determinants of distant progression and its impact on patient survival particularly in adults have not been thoroughly characterized. METHODS: This retrospective multicenter cohort study of 52 adult patients with DMG was analyzed for clinical and molecular predictors of distant tumor progression using gene panel sequencing and genome-wide DNA methylation arrays. RESULTS: Distant progression including leptomeningeal disease occurred in 10 out of 52 adult patients (19%), seven of which had a primary spinal tumor location (70%, p < 0.001) and almost 80% of patients with spinal DMG experienced distant progression. Across the entire cohort, distant progression was associated with worse progression free survival (PFS) (4.5 vs. 13 months; p = 0.037). However, we could not identify a genetic or methylation-based signature that was significantly correlated with the occurrence of distant progression. CONCLUSIONS: Adult DMGs with spinal location are at a high risk of early distant progression. As there were no molecular determinants of distant progression from differential methylation, copy number alterations (CNA) or panel sequencing, adult patients with DMG should undergo routine craniospinal MRI, particularly in spinal tumor location.