PDTM-28. THE CONTRIBUTION OF PAX GENES AS NOVEL TUMOR SUPPRESSORS IN GROUP 3 MEDULLOBLASTOMA
Bibliographic record
Abstract
Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor. Of the four distinct molecular MB subgroups, Group 3 MB has the worst prognosis, is highly metastatic, and is poorly defined with regard to the pathways that contribute to tumor progression. OTX2 is overexpressed/amplified in 80% of Group 3 MB, where it contributes to increased self-renewal and reduced neuronal differentiation. In order to identify genes associated with an OTX2 gene regulatory network in Group 3 MB cells, we mapped changes in active (H3K4me3) and repressive (H3K27me3) histone modifications following OTX2 silencing in Group 3 MB tumorspheres by ChIP-sequencing. Genes with significant changes in H3K27me3 profiles were associated with neuronal differentiation while genes that had significant changes in H3K4me3 profiles were associated with cell cycle progression. Interestingly, significant loss of H3K27me3 was observed for 114 transcription factors, indicating an overall de-repression of transcription factor expression following OTX2 silencing. Members of the PAX gene family were among the transcription factors de-repressed upon OTX2 silencing, and their role in MB progression has not been explored. Expression analysis in a cohort of 763 patient samples demonstrated that PAX3 and PAX6 expression is significantly lower in Group 3 MB. Reduced expression of PAX3 and PAX6 in Group 3 MB correlated with a significant reduction in overall patient survival. Following OTX2 knockdown in established and newly derived Group 3 MB cell lines, significant increases in PAX3 and PAX6 expression were observed providing further support for our ChIP-sequencing data. Finally, silencing of PAX6 expression resulted in an increase in cell growth suggesting a putative tumor suppressor role in Group 3 MB. Our ongoing and future studies include the further evaluation of putative divergent regulatory roles of OTX2 and PAX6 controlling neuronal differentiation in Group 3 MB.
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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 | 0.000 |
| 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".