Abstract PR09: <i>STAG2</i> mutations alter topologic organization of the genome and cis-mediated interactions
Bibliographic record
Abstract
Abstract STAG2 is one of the most recurrently mutated genes in human cancer, including in Ewing sarcoma, an aggressive bone tumor driven by the chimeric EWSR1-FLI1 transcription factor. We and others have shown that STAG2 mutations occurs in approximately 20% of Ewing sarcoma, leading most frequently to complete loss of function (LOF) of its protein. We also showed that STAG2 mutations were associated with poor outcome for these patients. However, functional mechanisms associated with these mutations are still poorly understood. STAG2 encodes an integral member of the cohesin complex, a ring-shaped multiprotein structure, which is important for proper sister chromatid cohesion and release during mitosis. Cohesin, together with CTCF, is also essential to shape the architecture of the genome through its ring structure that allows for chromatin loops formation. Here, we investigated STAG2 and STAG1 functions using isogenic proficient and deficient Ewing sarcoma models. Using extensive characterization of these models by transcriptomics and epigenetics approaches, we demonstrate that STAG2 LOF has a major impact on the expression of genes associated with enhancer features, highlighting STAG2 and EWSR1-FLI1 convergent effects. Using chromatin conformation capture methods, we further show that this transcriptomic modulation results from a STAG2 LOF specific topologic alteration of the genome. This work therefore unravels a new fundamental role of STAG2 in topologic organization of the genome and in gene regulation. This abstract is also being presented as Poster B53. Citation Format: Didier Surdez, Sakina Zaidi, Sandrine Grossetête, Virginie Raynal, Sylvain Baulande, Véronique Hill, Olivier Delattre. STAG2 mutations alter topologic organization of the genome and cis-mediated interactions [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr PR09.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".