Abstract A007: Integrative multiomic analysis reveals NOTCH signaling is derepressed by loss of PRC2 in malignant peripheral nerve sheath tumors
Bibliographic record
Abstract
Abstract Neurofibromatosis Type 1 syndrome (NF1) is a cancer predisposition syndrome caused by inheritance of one loss of function allele of the NF1 gene. NF1 patients can develop malignant peripheral nerve sheath tumors (MPNST), a deadly soft tissue sarcoma. MPNSTs develop after somatic loss of the wild-type NF1 allele, resulting in an increase in Ras-GTP activated signaling. This malignant transformation is still not completely understood, but loss of TP53 or CDKN2A/2B function and the polycomb repressor complex 2 (PRC2) are common events during the transition to MPNST. SUZ12, EED and EZH2 are core components of PRC2, which is responsible for trimethylation of Histone H3 at lysine 27 (H3K27me3), a repressive epigenetic mark that silences genes through formation of heterochromatin. We hypothesized loss of PRC2 has direct and indirect effects on gene expression resulting in MPNSTs. PRC2 loss may result in altered topologically associated domains, which can affect access of promoters by distal enhancers. Altered gene expression leads to deregulation of cell differentiation and proliferation controls, promoting the transition to MPNSTs. The purpose of this study is to identify epigenomic vulnerabilities of MPNSTs using multi-omics to elucidate more effective treatments. We have engineered NF1-deficient human Schwann cells with or without concomitant loss of function SUZ12 or EED mutations. We found major epigenomic changes in the histone code of SUZ12 mutants including complete loss of H3K27me3 with concomitant gain in H3K27 acetylation. SUZ12-deficient cells also become hypersensitive to histone deacetylase inhibitors. RNA sequencing has revealed many differentially expressed genes when SUZ12 and NF1 are lost in our engineered cell lines. Preliminary results show 92 differentially expressed genes that are common to PRC2-deficient MPNSTs and engineered cell lines. 824 genes are common between our engineered cell lines where 686 of these are derepressed when SUZ12 or EED are lost with NF1. We also identified an increase in differentially expressed genes when PRC2 is lost with NF1 versus NF1 loss alone. Comparing these to genes expressed in MPNST patient samples, we have identified potential drivers of MPNST generation. Pathway enrichment analysis on differentially expressed genes indicates many upregulated cancer related pathways when PRC2 is lost. We found NOTCH and Sonic Hedgehog signaling are common to all comparisons. NOTCH signaling has been implicated in Schwann cell development. These are currently being validated via Western blot. Proteomics data will also be compared to the findings. Citation Format: Minu Bhunia, Christopher M. Stehn, Mahathi Madala, Kyle Williams, Alex Larsson, Tyler Jubenville, Suganth Suppiah, Gelareh Zadeh. Integrative multiomic analysis reveals NOTCH signaling is derepressed by loss of PRC2 in malignant peripheral nerve sheath tumors. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A007.
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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) | 0.002 | 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".