CBMT-06. LOWER GRADE ISOCITRATE DEHYDROGENASE (IDH) MUTANT GLIOMAS METABOLICALLY MIMICKING GLIOBLASTOMA (GBM) EXPRESS HIGHER R:S 2-HYDROXYGLUTARATE RATIOS RELATIVE TO NON-GBM-MIMICKING IDH MUTANT GLIOMAS
Bibliographic record
Abstract
Glioma patients continue to carry a very poor prognosis despite maximal therapy, urging for the development of novel therapies. Previous studies have identified mutations of metabolic enzymes directly regulating cellular metabolism, specifically, isocitrate dehydrogenase (IDH1/2) mutation. IDH1/2 mutations occur early in glioma pathogenesis and result in the accumulation of oncometabolite 2-hydroxylgutarate (2-HG), with the preferential accumulation of the R relative to the S enantiomer of 2-HG. This metabolic reprogramming may help explain treatment resistance and highlight potential metabolic pathways involved in tumorigenesis. To investigate the metabolic profile of a cohort of gliomas, we used ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to detect a set of 689 metabolites in 90 IDH1 mutant and IDH1 wildtype gliomas. Unsupervised consensus clustering identified two distinct metabolic subgroups of gliomas: metabolic group 1, which consists of only IDH1 mutated tumors (n=30) and metabolic group 2, which consists of all IDH1 wildtype tumors and a subset of IDH1 mutated tumors (n=60). We therefore, termed these IDH1 mutated tumors in metabolic group 2 as “GBM mimickers”. Importantly, comparison of IDH mutant tumors from metabolic group 1 versus the GBM mimickers showed distinct R:S 2-HG ratio differences, specifically with the GBM mimickers expressing significantly higher R:S 2-HG ratios (mean R:S 2-HG 2421.44 vs. 625.46, p=0.014). Moreover, the GBM mimickers showed significantly decreased progression free survival (20 months vs. 49 months, p<0.05, respectively) and increased tumor enhancement on imaging versus their IDH1 mutated counterparts in metabolic group 1 (100% vs. 37.5%, p<0.0001), suggesting that R:S 2-HG ratio may be a marker of poor outcome. CONCLUSION: Our data supports distinct metabolic subtypes of IDH mutant gliomas, and highlights the use of R:S 2-HG ratio as a potential marker of poor outcome in IDH mutant gliomas.
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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 | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".