Abstract
Diffuse midline glioma (DMG) is the second most common malignant pediatric brain tumor, occurring predominantly in children 3–10 years old. Recent studies suggest considerable epigenetic, genomic, and clinical diversity within this entity. This is a retrospective study of patients with DMG at Memorial Sloan Kettering Cancer Center whose tumor underwent comprehensive DNA panel sequencing with MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) profiling. We identified 66 patients, divided into three age groups: 0-15 years (Pediatric, 34.3%), 15-39 years (Young Adult 41.8%), and over 39 years (Adult 22.4%). H3 K27M mutations in our cohort consisted of H3-3A mutations (94%) followed by H3-C2 (3%) and H3-3B (3%). Among the Pediatric group, TP53 alterations were present in 61% of patients; PDGFRA in 35%, ATRX in 17%, KIT in 17% and NF1 in 4%, along with pathway alterations in the RTK-RAS pathway in 61% and PI3K pathway in 39%. Within the Young Adult age group, TP53 was altered in 61% of patients; PDGFRA in 11%, ATRX in 29%, KIT in 4%, NF1 in 32%, RTK-RAS in 64% and PI3K pathway in 14%. In adults, we noted TP53 mutations in 60% of patients, PDGFRA in 47%, ATRX in 0%, KIT in 33%, NF1 in 40%, and pathway alterations in RTK-RAS in 93% of patients, PI3K in 47%. Median tumor mutation burden (TMB, mut/mb) values are as follows: Pediatric: 2.6, Young Adult: 3.5, and Adult: 4.1 (p=0.02). Mutations in TP53 were consistent throughout all age groups. RTK-RAS pathway alterations were similar in those under 39 years (61% and 64%), but overwhelmingly present in adults (93%). PI3K pathway mutations were less common in young adults. These findings highlight the differences and similarities in secondary driver alterations among patients with DMG, which may have important implications for understanding age-related differences in outcomes and therapeutic opportunities.