Chromosomal instability degrades developmental phenotypes essential for anti-GD2 immunotherapy outcomes in high-risk neuroblastoma
Bibliographic record
Abstract
High-risk neuroblastoma (HR-NBL) is a pediatric malignancy that arises during sympathoadrenal development and expresses the surface disialoganglioside GD2. Monoclonal anti-GD2 immunotherapy is a mainstay of HR-NBL treatment; however, it is associated with severe toxicities. Genomic correlates of outcomes following multimodality therapy containing anti-GD2 immunotherapy are limited. We profile 840 tumors and identify actionable ALK gene fusions in HR-NBL. We leverage fetal sympathoadrenal single-cell RNA sequencing to characterize patients with improved post-multimodality outcomes. We demonstrate that patients with improved outcomes have tumors that upregulate noradrenergic and metabolic phenotypes characteristic of mature sympathoblasts-a fetal sympathoadrenal cell population. We show that loss of these developmental phenotypes is mediated by chromosome 11q loss. Targeted analysis of 19 biopsy pairs identifies significant clonal evolution and accumulation of cell-cycle mutations following multimodality treatment. Collectively, we identify chromosomal instability-specifically 11q loss-as key in degrading developmental phenotypes critical for outcomes following multimodality therapy containing anti-GD2 immunotherapy.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| 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 | 0.000 | 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".