Abstract BACKGROUND Diffuse leptomeningeal glioneuronal tumors (DLGNT) with 1q gain (1q+) display aggressive clinical behavior. We sought to better describe the clinical characteristics of patients with DLGNT and identify molecular drivers and therapeutic vulnerabilities of DLGNT with 1q+. METHODS DLGNTs were collected from multiple institutions, sent for methylome array and if quantity-sufficient, were subjected to RNA-seq, proteome, and phosphoproteome profiling. Wherever available, clinical data was collected. RESULTS Twenty DLGNTs (13 with 1q+, 7 without 1q+) were collected. Clinical data was obtained on 15 patients (8 with 1q+, 7 without 1q+). The median progression-free survival (PFS) was 17.5 months for those with 1q+ tumors, compared to 51 months for those without (p=0.058). All with 1q+ tumors (n=4) that received CSI radiotherapy progressed (median 12 months), compared to none without (n=3) (p=0.12). There were no responses (complete or partial) in 1q+ tumors that received chemotherapy (n=8), with 2 progressions on therapy. In tumors without 1q+ that received chemotherapy (n=6), 2 responded (1 complete, 1 partial) and 1 progressed on therapy. For 1q+ tumors that received targeted therapy (n=6), there were no responses and 2 progressions on therapy, compared to 1 response and 1 progression for tumors without (n=3). Gene Set Enrichment Analysis of all differentially methylated regions demonstrated enrichment of genes acting in mRNA processing, transcriptional regulation, p53 signaling, TGF-β receptor signaling, and T cell receptor signaling in 1q+ tumors. It identified genes with transcription factor (TF) binding sites for TFs involved in MAPK, PI3K/AKT/mTOR, WNT, and p53 pathways. Consistent with these results, hypomethylated genes at chromosome 1q in 1q+ tumors are positive regulators of MAPK, PI3K/AKT/mTOR, WNT, and p53 signaling. CONCLUSIONS DLGNT with 1q+ were more refractory to current treatment options. We identified putative molecular drivers in 1q+ tumors. Our findings suggest therapy targeting the multiple affected pathways should be considered.