<i>BRCA1</i> is a molecular correlate of cell proliferation in human brain development and in Group 3 and 4 medulloblastoma
Bibliographic record
Abstract
ABSTRACT The role of the BRCA1-mediated DNA damage repair pathway in regulating human brain development remains unknown, although it has been studied in mouse development. We report evidence for breast cancer type 1 susceptibility protein (BRCA1) being a molecular correlate of proliferation in human neural progenitor cells and in medulloblastoma (MB), a malignant pediatric hindbrain cancer whose cells resemble undifferentiated neural stem cells. In a computational search for molecules potentially keeping Group 3 (G3) and Group 4 (G4) MB tumour cells in a state of stalled differentiation, BRCA1 emerged as a leading candidate gene. We surveyed four independent transcriptomic datasets collectively spanning 142 human developing brain samples, multiple brain regions, and over 1.7 million single cells, and found that BRCA1 transcription is consistently enriched in human neural stem and progenitor cells, relative to differentiating or mature neurons. Across the human lifespan, BRCA1 expression is enriched in the brain during early development, particularly the first trimester of gestation. By analyzing 714 tumours, the largest transcriptomic survey of MB tumours to date, we found that BRCA1 expression is increased in carriers of isochromosome 17q (i17q) aberrations and in G4 MB tumours. Increased BRCA1 expression is associated with worse prognosis in G3 and G4 MB. In the developing cerebellum as well as in the cancer context, BRCA1 expression is correlated with transcription of the cell cycle and DNA damage repair pathways. When considered with previous mouse studies, our work is consistent with a model in which BRCA1 promotes genome surveillance in neural progenitors during human brain development and in G3 and G4 MB tumour growth, thus supporting proliferation.
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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 | 0.001 | 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) | 0.001 | 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".