EPCO-06. MOLECULAR DETERMINANTS OF EVOLUTION AND PROGNOSIS AMONG DIFFUSE LOWER GRADE ASTROCYTOMAS
Bibliographic record
Abstract
Abstract Gliomas with wild type (WT) isocitrate dehydrogenase (IDH) are considerably more aggressive than those with mutant IDH. To identify putative drivers of the distinct progression trajectories of IDH WT and mutant disease, we analyzed transcriptomes of lower grade astrocytomas (LGAs; grade 2–3) with retention of 1p and 19q from The Cancer Genome Atlas (TCGA; n = 347). Compared to IDH mutant LGAs, we found that PDGF signaling was significantly enriched in IDH WT LGAs and that PDGFA was the top overexpressed gene in this pathway. We identified copy number gains of chromosome 7 in WT LGAs, and methylation of the PDGFA promoter in mutant LGAs, as candidate mechanisms for the differential expression of PDGFA. High PDGFA expression and low PDGFA promoter methylation were significantly associated with poor survival in all LGAs. We also found that PDGFA expression was positively associated with aneuploidy and extracellular matrix-related immunosuppressive features in WT LGAs, underscoring the role of PDGFA as a secreted mitogen. Finally, we show that the proportion of p53 pathway mutations increase significantly with grade in IDH WT gliomas. Taken together, our findings suggest that IDH WT LGAs evolve to higher grades, and ultimately to GBM, by progressive inactivation of the p53 pathway - functioning in concert with a background of increased PDGFA expression. These data emphasize the scope of genomic reprogramming that occurs in gliomas in relation to IDH mutations and further highlight the role of PDGFA in glioma formation, progression, and prognosis. Going forward, this work provides critical biological insight that may inspire new therapeutic strategies to suppress the transformation of IDH WT LGAs to higher-grade cancers.
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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 | 0.001 |
| 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".