Abstract B30: ARID1A is a haploinsufficient tumor suppressor for N-Myc transformation of neural crest cells
Bibliographic record
Abstract
Abstract Large segmental chromosomal alterations are common to cancer and a feature of high-risk neuroblastoma (NBL). Though they are early or initiating events in cancer, including often being found in precancerous lesions, their contribution to tumorigenesis is poorly understood. An unproven model is that these changes promote cancer through the cumulative effect of multiple dosage-sensitive genes. Loss of heterozygosity (LOH) at 1p36 is a frequent structural rearrangement in a broad range of human cancers including NBL. Approximately 70% of MYCN amplified NBL have 1p36 LOH with both mutations independently contributing to tumor aggressiveness in NBL. Two tumor suppressor regions have been proposed to exist in 1p36, a distal and proximal region, which have MYCN-independent and dependent roles. Through CRISPR/Cas9 genome editing of primary mouse neural crest cells (NCCs), a source for NBL, we found that loss of the chromatin remodeling factor Chd5 conferred most of the tumor-suppressor effects of 1p36 LOH in in vitro cell transformation assays in cells with endogenous levels of N-Myc. In contrast, when N-Myc was overexpressed, tumor evolution of NCCs genome edited to have randomly sized 1p36 deletions showed a reduction in tumor latency that significantly correlated with deletion of Arid1a. The Arid1a deletions that were selected for ranged from small indels up to large 1p36 deletions, indicating that large deletions are tolerated to achieve loss of a single critical tumor suppressor. Further, using lentiviral Cre-induced deletion of floxed Arid1a in isolated NCCs, we found that Arid1a is a haploinsufficient tumor suppressor in MYCN-driven transformation of NCCs. As Arid1a is a subunit of the chromatin remodeling complex SWI/SNF, which is mutated in 20% of cancers, Arid1a synthetic lethal therapies are being developed for adult malignancies. We are currently verifying those proposed therapies in NBL and are using small-molecule screening of cells lines derived from Arid1a wild-type, het, or null tumors to identify additional synthetic lethalities. Our findings indicate that context, such as the status of MYCN as an oncogene, dictates which 1p36 gene is the critical tumor suppressor, establishing 1p36 LOH as multifaceted not cumulative, as was previously believed. Citation Format: Kirby Wallace, Jesus Garcia-Lopez, Joel Otero, Rachelle Olsen, Chelsea DeVaux, Ashton King, Andrew Davidoff, Kevin Freeman. ARID1A is a haploinsufficient tumor suppressor for N-Myc transformation of neural crest cells [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 B30.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.002 |
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".