GENE-15. CHARACTERIZATION OF DIFFERENTIAL 5-HYDROXYMETHYLCYTOSINE IN IDH1 MUTANT VERSUS IDH1 WILD-TYPE HIGH-GRADE GLIOMAS
Bibliographic record
Abstract
Glioblastoma demonstrates significant epigenetic dysregulation, with subgroup differences highlighted by the Glioma CpG-island methylator phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-hydroxymethylcytosine (5hmC) has been implicated in IDH1 wild-type tumors (Johnson et al, Nat Commun Nov 2016), however its role in IDH1 mutant gliomas remains undescribed. We examined the 5hmC and methylcytosine (5mC) profiles in high grade (WHO III/IV) IDH1 mutant (n = 12) and IDH1 wild-type (n = 9) tumors using the Illumina EPIC platform. Gene expression was profiled using the Affymetrix Human Gene 2.0 ST array. Cumulative density plots for mean 5hmC across IDH1 mutant samples demonstrated 5hmC accumulation within the last 10th percentile. To focus on probes with greatest 5hmC abundance, we assessed probes in the top 1% mean 5hmC. In addition, differentially methylated (DMR) and hydroxymethylated (DHMR) regions were identified using the R package “ChAMP” comparing IDH1 mutant to wild-type tumors. No significant difference in 5hmC between groups was evident, with a mean 5hmC of 18.9% and 15.7% for IDH1 mutant and wild-type, respectively. Top 1% 5hmC probes preferentially marked Open Sea and CpG island shores and predominantly associated with intronic genomic regions. Enhancer probes were enriched in both subgroups. Of genes defining the G-CIMP phenotype, 28/50 were differentially methylated, while 22/50 G-CIMP genes were differentially hydroxymethylated suggesting that 5hmC may contribute to aberrant methylation defining G-CIMP tumors. Among 1367 differentially expressed genes, 48 demonstrated positive Spearman correlation between 5hmC and gene expression (r=0.5 or greater, p < 0.05) including genes implicated in gliomagenesis and novel candidates. FAM171B demonstrated the highest correlation (r = 0.80, p = 0.00002). DHMR genes were enriched for members of several biologic processes (including nervous system development, cell adhesion, cell-cell signalling, cell differentiation, response to hypoxia) and pathways (including ERK signalling, Wnt/Hedgehog/Notch signalling, targets of C-MYC transcriptional regression).
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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) | 0.005 | 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".