Abstract 1549: The tumorigenesis model in DGCR8 associated schwannomatosis
Bibliographic record
Abstract
Abstract Purpose: Schwannomatosis is an inherited disorder that affects Schwann cells from peripheral nerves. It is diagnosed when multiple schwannomas occur in the absence of bilateral vestibular schwannomas. The two main genes associated with this disorder are SMARCB1 and LZTR1 both on chromosome 22q (Chrm22q). Somatic inactivation of NF2, downstream of SMARCB1, is observed in most schwannomas. The accepted model of schwannomatosis involves multiple hits over three steps to inactivate LZTR1 or SMARCB1 together with NF2. Following this pattern, most of the LZTR1/SMARCB1-schwannomas acquire a somatic loss of Chrm22 (thus deleting the three genes) and a somatic mutation affecting the remaining wild-type NF2 copy on the GPV allele. Several studies have postulated the plausible existence of other susceptibility genes predisposing to schwannomatosis and the likelihood of those being localized in Chrm22q. Last year we identified a GPV in the microprocessor DGCR8 (c.1552G>A; p.E518K) located in the Chrm22q11 region, as responsible for a familial form of schwannomatosis and multinodular goiter (Rivera et al JCI, 2020). Our goal is to clarify the role of DGCR8 as a novel tumor susceptibility gene and the tumorigenic mechanisms that lead to DGCR8-schwannomatosis. Methods: We searched for patients affected of schwannoma and thyroid tumors. By whole exome sequencing we identified the same DGCR8 (c.1552G>A; p.E518K) variant in one patient. We then collected a total of 13 DGCR8-schwannomas from carriers. Eleven tumors were subjected to WES and two tumors were subjected to a NGS targeted panel covering all known schwannoma genes in Chrm22q. Results: We report the second case of a patient with peripheral schwannomatosis and thyroid alterations caused by the germline pathogenic variant E518K in DGCR8. Loss of Chrm22q was seen in all 13 tumors analyzed. While all tumors had at least one alteration of NF2, 4 tumors had no somatic mutations on the retained (not deleted) allele (30.8%). Given that DGCR8 localizes 5’ of LZTR1, the second step (LOH) leads to the deletion of DGCR8 and the three bona fide schwannoma genes (LZTR1, SMARCB1 and NF2) adding up to a total of 6 hits in a 3-step model. Suggesting that the path to tumorigenesis driven by DGCR8 requires the loss of the wild type allele of Chrm22q and in more than two thirds of the tumors a complete inactivation of NF2 occurs. Conclusion: Our findings highlight DGCR8 as a schwannomatosis gene mapping to the Chrm22 cluster of tumor suppressors that cooperate to promote tumorigenesis in Schwann cell and pinpoints an important role of miRNA regulation in this process. Citation Format: Clara Nogué, Anne-Sophie Chong, Elia Grau, HyeRim Han, Eduard Dorca, Carla Roca, Jose Luis Mosquera, Conxi lazaro, William D. Foulkes, Joan Brunet, Bárbara Rivera Polo. The tumorigenesis model in DGCR8 associated schwannomatosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1549.
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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 | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".