PNR-08NEWLY DISCOVERED ONCOGENES DRIVING AND MAINTAINING CHOROID PLEXUS CARCINOMA PROVIDE POTENTIALLY DRUGGABLE TARGETS
Bibliographic record
Abstract
Choroid plexus carcinomas (CPCs) are poorly understood and frequently lethal brain tumours with few treatment options. The role of surgical treatment is well established, but the benefit of either chemotherapy or radiotherapy remains controversial. There is a great need for new, effective and non-toxic treatments. Using a mouse model of the disease and a large cohort of human CPCs, we performed a cross-species, genome-wide search for oncogenes within syntenic regions of chromosome gain. Our data identified a group of concurrently gained oncogenes, TAF12, NFYC, and RAD54L that cooperate in the formation and progression of CPC and reveal potential avenues for therapy. These oncogenes are co-located on human chromosome 1p32-35.3 and mouse chromosome 4qD1-D3 and were amplified in tumours of both species. TAF12 and NFYC are transcription factors that regulate the epigenome, whereas RAD54L plays a central role in DNA repair. Early in postnatal life, aberrantly proliferating choroid plexus epithelium cells develop increasingly abnormal genomes leading to genotoxic crisis. While most of these cells undergo cell death, presumably through TP53-independent mechanisms, a fraction acquire aberrant DNA repair and epigenome remodeling capacity, including amplification of TAF12, NFYC, and RAD54L. This enables them to tolerate an aberrant but stable genome and drive further transformation.Validation of aberrant DNA repair as a requirement for CPC formation and maintenance could lead to new therapies, as inhibition of DNA repair enzymes should result in intolerable DNA damage. To test this hypothesis we will utilize compounds inhibiting RAD54/ATR/ATM-driven homologous recombination up-regulation at a crucial stage of tumour development.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".