Loss of NF1 Accelerates Uveal and Intradermal Melanoma Tumorigenesis, and Oncogenic GNAQ Transforms Schwann Cells
Bibliographic record
Abstract
ABSTRACT: NF1 encodes the multifunctional tumor suppressor protein, neurofibromin, which is best known for its causative role in neurofibromatosis type 1 and in regulating MAPK signaling. Neurofibromin, in a context-specific manner, is involved in various tumorigenic processes, including those in melanocytes. This study investigated whether NF1 loss can collaborate with oncogenic GNAQ to promote melanoma in the dermis or eyes, in which the Gαq pathway is almost always activated. We found that heterozygous 17q11.2 loss that includes the NF1 locus is a recurrent phenomenon in human intradermal and uveal melanomas described in the literature. We studied the effects of Nf1 haploinsufficiency in mice expressing oncogenic GNAQQ209L in melanocytes and Schwann cells of peripheral nerves using the Plp1-creERT transgene with tamoxifen at 5 weeks of age. Nf1 haploinsufficiency accelerated melanoma formation and/or growth. RNA sequencing analysis found significant pathways related to cAMP signaling and myogenesis. In addition, 20% of the differentially expressed genes were homologous to genes for which expression correlates with prognosis in human uveal melanoma. Unexpectedly, we found that GNAQQ209L alone was sufficient to drive cutaneous nerve sheath tumors, with one GNAQQ209L-expressing Nf1 haploinsufficient mouse also developing a plexiform variant. These tumors strongly resembled neurofibromas. We searched the cBioPortal for Cancer Genomics database and found plexiform neurofibromas with the GNAQT96S hotspot mutation. The Plp1-creERT; GNAQQ209L model with tamoxifen at 5 weeks may be useful as a preclinical model for neurofibroma. Our studies emphasize the importance of GNAQ and NF1 in regulating neural crest–derived cells existing in a dermal-like environment. SIGNIFICANCE: These results indicate that NF1 loss in intradermal and uveal melanomas is a potentially significant finding. They emphasize the importance of neurofibromin in cAMP signaling. They show for the first time that oncogenic GNAQ can transform Schwann cells in mice. The Plp1-creERT transgene with tamoxifen given at 5 weeks may be a particularly good strategy for modeling cutaneous neurofibroma and plexiform neurofibroma.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".