LG-01 * BRAF MUTATION AND CDKN2A DELETION DEFINE A CLINICALLY DISTINCT SUBGROUP OF CHILDHOOD SECONDARY HIGH-GRADE GLIOMA
Bibliographic record
Abstract
PURPOSE: To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG). METHODS: We retrospectively identified sHGG cases from a population-based cohort of 886 PLGG with very long clinical follow-up. Exome-sequencing and copy number alterations were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups was performed. RESULTS: sHGG was observed in 2.9% of PLGG (26/886). sHGG had a high frequency of non-silent somatic mutations compared to primary pediatric HGG (median 25/exome; P = .0042). Alterations in chromatin modifying genes and telomere-maintenance pathways were commonly observed while no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGG, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished secondary from primary HGG (P = .0023), while BRAF and CDKN2A alterations were rarely observed in PLGG which did not transform (P < .0001 and .0007 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median 6.65, 3.5-20.3 years versus 1.59, 0.32-15.9; P = .0389). Furthermore, 5-year overall survival was 75%□15% and 29%□12% for children with BRAF mutant and wild-type tumors, respectively (P =.024). CONCLUSION: BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance and targeted therapies to mitigate the outcome of sHGG.
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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 | 0.001 |
| 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".