Abstract A39: Molecular characterization of ETMRs reveals role for R-loop mediated genomic instability and new treatment options
Notice bibliographique
Résumé
Abstract Introduction: Embryonal tumors with multilayered rosettes (ETMRs) are aggressive brain tumors that occur mainly in infants. Patients face a very poor prognosis with a median overall survival of ~12 months after diagnosis. The tumors harbor in ~90% of all cases amplification of a miRNA cluster on chromosome 19 (C19MC) that is thought to be the driver of the disease. However, current treatment options are lacking as (a) the mechanisms downstream of C19MC are poorly understood and (b) the drivers in cases lacking the C19MC aberration are unknown. To develop better treatment protocols for ETMR patients, more insight is needed in what is driving these tumors and how that can be targeted. Materials and Methods: To investigate the genomic and epigenomic landscape of ETMR in depth, we collected 193 ETMR samples and 23 matched relapses and performed DNA methylation profiling on all and DNA (whole genome, whole exome, and panel) sequencing and mRNA and miRNA transcriptome analysis on a subset of them. The BT183 ETMR cell line was used for drug treatments. Results: Among the 22 tumors without C19MC amplification, we identified 8 cases with truncating DICER1 germline mutations in one allele and somatic missense mutations in the RNASE III domain in the other allele. No DICER1 mutations were identified in C19MC amplified cases. In addition, structural variations (SVs) affecting C19MC were found in 3 other C19MC nonamplified cases and amplification of another miRNA cluster, miR-17-92, in 2 other cases. However, despite the presence of different genetic aberrations, based on DNA methylation and transcriptome profiling no molecular subgrouping was observed within our cohort. Whole-genome sequencing revealed an overall low recurrence and conservation of SNVs but strong conservation of SVs from primary tumors to relapses, especially surrounding C19MC. Moreover, many newly acquired SNVs in the relapses are associated to a new cisplatin treatment-related mutational signature. SVs detected in ETMRs significantly colocalized with R-loops, structures that form upon a collision of replication and transcription and are associated to increased levels of chromosomal instability, which is frequently observed in ETMRs. Using a DICER1 KO model, we found that global deregulation of miRNAs led to increased levels of R-loops and R-loop associated chromosomal instability. Finally, we show that a combination of topoisomerase and PARP inhibitors is highly synergistic and strongly increased the levels of both R-loops and DNA damage in ETMR cells and effectively killed the cells. Conclusions: Our results show that genomically instable ETMR cells are vulnerable to further increases in chromosomal instability, knowledge that may lead to new treatment strategies for ETMR patients and possibly other cancers with high levels of R-loops. Citation Format: Sander Lambo, Susanne Grübner, Tobias Rausch, Sebastian Waszak, Christin Schmidt, Sonja Krausert, Loreen Weichert, Aparna Gorthi, Carolina Romero, Annie Huang, Julia Schueler, Jan Korbel, Alexander Bishop, Stefan Pfister, Andrey Korshunov, Marcel Kool. Molecular characterization of ETMRs reveals role for R-loop mediated genomic instability and new treatment options [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 A39.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».