Multiple <i>FGFR1</i> mutations modulate tumorigenic mechanisms in glioneuronal tumors
Bibliographic record
Abstract
Abstract FGFR1 genetic alterations are associated with human diseases, including brain tumors. We reported multiple FGFR1 mutations in familial and sporadic cases of low-grade glioneuronal tumors, suggesting intrinsic mechanisms of selective pressure toward FGFR1 multiple events arising in the context of a quiet genome. To decipher the molecular mechanisms triggered by multiple FGFR1 mutations, we have mapped the proximal interactome of wild-type, single-and double-mutant FGFR1 proteins through a BioID-MS approach. Our data reveals novel oncogenic functionality for the two hotspots N546K and K656E, linked to evasion of lysosomal degradation. We identified a modulatory role played by the susceptibility variant R661P, which hampers the oncogenic potential of both hotspot mutations by rescuing receptor degradation and reducing N546K affinity for the downstream effector PLCγ. The R661P variant alone abolished the self-renewal capacity of oligodendroglioma cells and showed downregulation of genes involved in neurodevelopment and neuro-glial cell fate decisions, both aspects overcome in the double mutants. This study sheds light on the oncogenic effects associated with FGFR1 alterations and their recurrence in low-mutation burden and therapy naïve tumors.
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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 | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| 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".