HGG-11. Integrated molecular profiling of H3 wild-type diffuse paediatric-type high-grade glioma
Bibliographic record
Abstract
Abstract Background Within the WHO2021 CNS Tumour Classification, oncohistone H3-mutations define around half of paediatric-type diffuse high grade glioma, however the remaining tumours (H3-WT-PDHGG) are less well described. Methods Published and unpublished DNA sequencing from n = 1601 H3-WT-PDHGG cases were integrated with n = 1847 cases with methylation array profiling, along with bulk (n = 251) and single-cell (n = 65) RNAseq data. Results Within H3-WT high-grade glioma, a total of 11 MNP12.8-defined subgroups were found to have a peak incidence <18years, excluding infant hemispheric glioma. Clustering of methylation data by tSNE/UMAP highlighted two highly distinct superclusters, with multiple subgroups within each. Supercluster_I was defined by radiation-induced secondary and/or hypermutant tumours, incorporating HGG-E (n = 44), cerebellar-enriched tumours (n = 38), and the paediatric RTK1 group (n = 295), further split into A, B and C subgroups. There were profound molecular differences between RTK1A and B/C subgroups, with 1A harbouring few CNAs and many more SNVs (SETD2, NF1), even in the absence of a hypermutator phenotype (also enriched compared to RTK1B/C), as well as a significantly longer overall survival. Distinct from these subgroups was Supercluster_II, which included pedHGG-RTK2A/B (n = 117), but also pedHGGA/B (n = 84) and pedHGG-MYCN (n = 122) subgroups, in addition to the predominantly H3-WT DMG-EGFR (n = 86). Although seemingly disparate, a common feature of these tumours was a highly infiltrative phenotype, either involving multiple cerebral lobes (gliomatosis cerebri) or thalami (bithalamic glioma). Analogous to pedHGG-RTK1, RTK2A harboured few CNAs and more CNVs (BCOR, PIK3CA), and a longer survival compared with 2B. Integrating subgroup-specific differential methylation and gene expression identified subgroup-specific epigenetic regulation of numerous developmentally-restricted transcription factors associated with their distinct neurodevelopmental origins; combining deconvolution approaches to bulk analyses with integrated scRNAseq allowed for identification of subgroup-specific immune cell annotation. Conclusion H3-WT-PDHGG segregate into two major classes with common clinical features, but each with multiple subgroups harbouring key molecular and phenotypic differences.
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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 | 0.001 |
| 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) | 0.001 | 0.000 |
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".