DIPG-26. CLINICAL AND GENOMIC ANALYSIS OF H3K27M-DMG LONG-TERM SURVIVORS REVEALS ENRICHMENT IN MAPK PATHWAY ALTERATIONS

INTRODUCTION: H3K27M-mutant diffuse midline gliomas (H3K27M-DMGs) share a generally poor prognosis with a median overall survival (OS) of 9–12 months. However, patients with histone-mutant central nervous system (CNS) tumors and long-term survival (LTS) have been reported, in some instances beyond three years. We aim to determine characteristics of patients with H3K27M-mutant CNS tumors associated with LTS (OS>36 months). METHODS: We performed a multi-site and literature case review of patients with confirmed H3K27M-DMG (including H3.1, H3.3, or by IHC) and LTS (OS>36 months) with extraction of demographic, diagnostic, molecular, therapeutic, and outcome data. We obtained a final cohort of 72 patients (median age 14 years, IQR 7-31 years). A control cohort of 453 patients with confirmed H3K27M-DMG and OS<18 months was created through literature review. Between the cohorts, demographic and clinical differences were compared for statistical significance (unpaired t-test and chi-squared test), excluding unknown variables, and frequent genetic alterations were compared. RESULTS: There was no association with H3.3 versus H3.1 when comparing LTS (15% H3.1) and control (13.6% H3.1) cohorts. Alterations in MAPK pathway genes [NF1 (n=10), FGFR1 (n=10), and BRAF (n=9)] were more frequent in the LTS cohort, with H3.3/BRAFV600E co-mutation being reported in 8/72 (11%) LTS patients and only 5/453 (1.1%) control patients. The LTS group had a greater proportion of patients with non-infiltrative (17.5%) and low-grade (26.6%) histology tumors than the control group (1.7%, p<0.001 and 11.4%, p=0.001, respectively). DNA methylation analysis and RNA sequencing are currently being performed for 29 LTS patients to determine molecular sub-groups within H3K27M-DMG with improved prognosis. CONCLUSIONS: Our early findings in this ongoing study suggest that both histological and molecular characteristics of H3K27M-DMG influence survival. We identify enrichment of alterations in MAPK pathway-related genes in patients with LTS. These findings hold promise for further defining and classifying H3K27M-DMG to improve prognostication.