Abstract 4318: Identifying drivers of SMARCA4/BRG1-deficient SCCOHT tumorigenesis by integrative multi-omic analysis
Bibliographic record
Abstract
Abstract Over 94% of small cell carcinomas of the ovary, hypercalcemic type (SCCOHT), a rare and aggressive form of ovarian cancer, have mutations and concomitant protein loss in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. SCCOHT tumors rarely have secondary mutations, making them an excellent model for understanding the role BRG1 and SWI/SNF complexes play in tumor suppression. We hypothesize that BRG1 loss drives SCCOHT tumorigenesis by altering chromatin accessibility and gene expression. We have previously shown that BRG1 re-expression in SCCOHT cell lines suppresses cell growth and induces an elongated, neuronal-like morphology. To identify the top genes and transcription factors driving SCCOHT tumorigenesis, we performed ATAC-seq and RNA-seq in a SCCOHT cell line +/- BRG1 re-expression. BRG1 re-expression increased overall chromatin accessibly, shown by an increase in the number of ATAC-seq peaks. ATAC peaks gained following BRG1 re-expression were enriched in transcription factor binding motifs from FOS/JUN/AP-1, TEAD, and SOX family members. RNA-seq analysis demonstrated that BRG1 re-expression upregulated more genes than those downregulated, consistent with the increase in ATAC-seq peaks. Preliminary pathway analysis identified gene enrichments in epithelial-mesenchymal transition pathway and extracellular matrix remodeling following BRG1 re-expression, consistent with the observed morphology change. Cell types enrichment analysis (xCell) identified a shift from a mesenchymal stem cell-like gene signature in the control SCCOHT cells to an epithelial cell-like gene signature following BRG1 re-expression, further suggesting a possible mesenchymal-epithelial transition in SCCOHT cells after BRG1 re-expression. Future studies include integration of the ATAC/RNA-seq data to further identify correlations between gene expression changes and enriched transcription factor binding motifs, integrative ChIP-seq analysis for BRG1 following re-expression, and proteomic analyses. These studies will uncover the key genes, proteins, and transcription factors affected by BRG1 loss in other adult cancers, provide insight into BRG1's role in SCCOHT tumorigenesis, and potentially yield novel therapeutic targets. Citation Format: Krystal A. Orlando, Jesse R. Raab, Jessica D. Lang, William P. Hendricks, Yemin Wang, David G. Huntsman, Jeffrey M. Trent, Joel S. Parker, Bernard E. Weissman. Identifying drivers of SMARCA4/BRG1-deficient SCCOHT tumorigenesis by integrative multi-omic analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4318.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".