PATH-07. GENOMIC AND IMMUNE ANALYSIS OF PRIMARY REPLICATION-REPAIR DEFICIENT (RRD) GLIOMAS REVEALS THREE SUBGROUPS WITH DISTINCT DRIVERS AND RESPONSE TO IMMUNOTHERAPY: AN IRRDC REPORT.
Bibliographic record
Abstract
Abstract BACKGROUND Replication-repair deficiency (RRD) caused by germline/somatic defects in mismatch repair (MMRD) and/or polymerase-proofreading genes (PPD) drives 5-10% of high-grade gliomas in children, adolescents, and young adults (CAYA). Despite harbouring high mutation-burden (TMB), the basis of their heterogenous responses to immune-checkpoint inhibitors (ICI) is unknown. METHODS We performed multi-omic and immune analyses on human RRD-glioma specimens and developed murine models to investigate their differential responses to ICI. RESULTS RRD-gliomas in 202 CAYA-patients uniformly harbored high genomic microsatellite-instability and hypermutation (median TMB: 302-mutations/megabase), with specific MMRD mutational signatures contributing to frequent mutations in TP53 (88%), ATRX (83%), RAS/MAPK (77%) and IDH1/2 (17%). Strikingly, common pediatric mutations (K27M, G34R/V and BRAF;p.V600E) unrelated to MMRD signatures were absent, and a unique methylation profile distinct from non-RRD gliomas was observed. Molecularly, RRD-gliomas segregated into three genomic subgroups: RRD1 (MMRD+PPD; 56%), RRD2 (MMRD-only; 27%), and RRD3 (MMRD+IDH1/2; 17%). RRD1 included glioblastomas that developed early in germline CMMRD patients across the cerebral hemispheres and posterior-fossa, harbored extreme TMB (median: 420-mutations/megabase), balanced copy-number profiles, and immunogenic PPD signatures. RRD3 predominated in Lynch syndrome, presented in older children, were located in the forebrain, harbored lower TMB (median: 31-mutations/megabase) and demonstrated specific chromosomal gains/losses. Enrichment for immune-resistant JAK-STAT signalling in the RRD2/RRD3 transcriptome, and presence of high CD8+ T-cells in RRD1-glioma microenvironment, correlated with significantly improved 24-month post-ICI survival of 75% in RRD1 versus 43% and 33% for RRD2/3, respectively (p < 0.0001). Genetically engineered mouse models recapitulated the immuno-genomic phenotype and ICI-responses of the human RRD-subgroups, allowing successful preclinical testing of combinatorial checkpoint-inhibition strategies. Significant temporal and spatial heterogeneity linked to genomic instability and post-therapy immune-escape were observed. CONCLUSION Our data emphasizes an immediate need to distinguish RRD-glioma subgroups in clinical practice and translate our preclinical discoveries to subgroup-specific ICI-based combinatorial clinical trials.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".