Integrative Genomics of Human Cerebellar Development and Group 3/4 Medulloblastoma
Bibliographic record
Abstract
Medulloblastoma (MB) comprises a group of heterogeneous pediatric neuronal neoplasms of the hindbrain with strong links to early development of the hindbrain. While Sonic Hedgehog MB arises in the upper rhombic lip (RL) granule cell lineage due to mutations that activate Shh signaling, and WNT MB arises in the lower RL due to mutations activating WNT signaling, little is known about the more common Group 4 (G4) MB, thought to arise in the unipolar brush cell (UBC) lineage. We demonstrate that somatic mutations in G4 MB converge on the Core Binding Factor Alpha (CBFA) complex, observing mutually exclusive alterations affecting CBFA2T2, CBFA2T3, PRDM6, KDM6A, and OTX2. CBFA2T2 is expressed early in the progenitor cells of the Homo sapiens cerebellar RL subventricular zone (RLSVZ), and G4 MB transcriptionally resemble these RLSVZ progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, allowing MB cells to spontaneously proceed along normal developmental differentiation trajectories. The unique nature of the split human RL, destined to generate the majority of the neurons in the human brain, with its high level of susceptible EOMES+ KI67+ UBC progenitor cells, likely predisposes our species to the development of G4 MB.
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How this classification was reachedexpand
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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".