HGG-12. Integrated molecular profiling of diffuse midline glioma, H3K27-altered
Why this work is in the frame
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Bibliographic record
Abstract
Abstract Background Diffuse midline glioma, H3K27-altered (DMG-H3K27) are recognised as a distinct type of paediatric diffuse high-grade glioma with dismal clinical outcome in the WHO2021 CNS classification, defined by an integrated diagnosis including the defining oncohistone H3 alterations. Increasing evidence suggests the presence of distinct subtypes, but these are not yet well-defined. Methods Published and unpublished DNA sequencing from n = 554 DMG-H3K27 cases were integrated with n = 498 cases with methylation array profiling, along with bulk (n = 112) and single-cell (n = 30) RNAseq data. Results Clustering of methylation data by tSNE/UMAP showed a clear separation largely driven by anatomical location, with a cluster enriched for pontine lesions (DIPG, n = 225) separating from those enriched in non-brainstem lesions such as the thalamus (n = 258), tightly linked to H3 variant status, and highly enriched for gain of chromosome 1q or loss of 5q, respectively. The two major methylation-based clusters were readily discriminated on the basis of differentially methylated regions driving differential expression and scRNA-seq, highlighting the previously reported developmental origins associated with location, but also novel markers associated with differences in tumour immune microenvironment, and distinct subpopulations of cells driving tumour infiltration. Co-segregating mutations in the MAPK pathway, incorporating variously BRAF_V600E, NF1, FGFR1, and PTPN11 may define a clinically distinct group of tumours in the thalamus, though PIK3R1 InDels and non-canonical BRAF mutations in the pontine DMGs highlighted aggressive tumours for which in vitro modelling reveals initial sensitivity but also complex resistance to targeted MAPK inhibition. These tumours were clearly distinct from those of the DMG-EGFR subgroup, which clustered by methylation with diffusely infiltrating H3-WT hemispheric glioma, harboured frequent chromosome 7 gains absent from other DMG subtypes, hypomethylation of the EGFR/IGF1R loci, and EZHIP overexpression. Conclusion DMG-H3K27 comprise multiple subgroups with clinically relevant phenotypes driven by molecular features which arise within the context of distinct anatomical locations.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.000 | 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 it