HGG-26. GENOMIC AND IMMUNE ANALYSIS OF PRIMARY REPLICATION-REPAIR DEFICIENT (RRD) GLIOMAS REVEALS THREE SUBGROUPS WITH DISTINCT DRIVERS AND RESPONSE TO IMMUNOTHERAPY: AN IRRDC REPORT

BACKGROUND: Replication-repair deficiency (RRD) caused by germline/somatic defects in mismatch repair (MMRD) and/or polymerase-proofreading genes (PPD) drives 5-10% of gliomas in children, adolescents, and young adults (CAYA). Although RRD-gliomas harbour high mutation-burden (TMB), the basis of their heterogenous biology, clinical behavior, and response to immune-checkpoint inhibitors (ICI) is unknown. METHODS: We analyzed the genome (whole exome, low-coverage genome), methylome, transcriptome (bulk, single-nuclei), and the immune-microenvironment of RRD-gliomas in a large cohort of IRRDC patients and correlated these with clinical outcomes and response to ICI. RESULTS: Gliomas in 202 CAYA-patients uniformly harbored hypermutation and genomic microsatellite-instability. Median TMB was 297-mutations/megabase, with frequent mutations in TP53 (90%), ATRX (85%), RAS/MAPK (80%) and IDH1/2 (15%). MMRD (but not PPD) mutational signatures contributed to the enrichment of driver mutations in POLE, IDH1, and TP53 while common pediatric mutations (K27M, G34R/V and BRAF;p.V600E) not driven by MMRD signatures were absent. Paired analyses suggested acquisition of novel variants driven by the mutational signatures that also impacted the immune microenvironment. Multi-omic analyses classified RRD-gliomas into three subgroups: RRD1 (MMRD+PPD; 60%), RRD2 (MMRD-only; 23%), and RRD3 (MMRD+IDH1/2; 16%). All RRD1-gliomas were glioblastomas with earlier age of onset, enrichment in CMMRD, arose at diverse locations including the posterior-fossa, classified in proximity to methylation-RTK1-subclass, exhibited balanced copy number profiles, harbored the highest TMB (median: 409-mutations/megabase), and immunogenic PPD signatures. Conversely, RRD3-gliomas were frequent in Lynch syndrome, presented at an older age, with predominant localization in the forebrain, more complex genomic instability, clustered in proximity to IDH1-gliomas, and harbored lower TMB (median: 33-mutations/megabase). RRD1-gliomas revealed the highest immune infiltrates with significantly improved median post-ICI survival of 52-months versus <12-months for RRD2/3 (p<0.0001). CONCLUSIONS: The distinct genomic subgroups of RRD-gliomas can explain their diverse clinical outcomes, highlighting the need for developing subgroup-specific, immune-directed treatment approaches for these patients.