GENE-26. MOLECULAR CHARACTERIZATION OF BENIGN AND MALIGNANT PERIPHERAL NERVE SHEATH TUMORS THAT OCCUR IN SPORADIC AND SYNDROMIC SETTINGS
Bibliographic record
Abstract
Neurofibromas, a peripheral nerve sheath tumor commonly associated with Neurofibromatosis Type 1, are broadly categorized as cutaneous or peripheral nerve neurofibromas (localized or plexiform lesions). More recently, atypical neurofibromatous neoplasm of unknown biological potential (ANNUBP) has been described and believed to be a premalignant tumor, although the oncogenic drivers of malignant transformation are poorly understood. In this study, we establish the spectrum of genomic drivers of neuronal tumors, benign and malignant, in sporadic and syndromic settings. We performed multiplatform genomic analysis of a total of 110 cutaneous neurofibromas, peripheral nerve neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). We performed methylation profiling and RNA sequencing on these tumors. Genomic data was bioinformatically analyzed to identify biologically relevant subgroups. Correlation and validation of key drivers were carried out using a series of IHC and in-vitro studies. Consensus clustering of methylation data reliably distinguished between cutaneous and peripheral nerve tumors that supports the theory that cutaneous neurofibromas have a distinct cell of origin. Copy number analysis (CNA) identified a loss of 9p in 35% of peripheral nerve neurofibromas. Consensus clustering of peripheral nerve neurofibromas alone identified 3 subgroups, with group 1 tumors having no CNAs and groups 2&3 enriched for tumors with CDKN2A loss (p < 0.05). In addition, ANNUBP were associated with the loss of CDKN2A (p < 0.05). Neurofibromas with loss of CDKN2A had gene sets associated with H3K27me3 and sarcomas upregulated, while genes associated with neuronal and Schwann cell signature downregulated. The genomic and epigenomic landscape of neurofibromas is poorly understood. We identified that atypical neurofibromas have loss of CDKN2A, suggesting that it is lost early in malignant transformation. The loss of CDKN2A may lead to dysregulation of H3K27me3, and further work is needed to identify the molecular alterations and pathways involved in malignant transformation.
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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 | 0.000 |
| 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".