Abstract 2980: Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations
Notice bibliographique
Résumé
Abstract Background The majority of high-risk neuroblastomas initially respond to chemotherapy, but over half of patients experience therapy-resistant relapses. The molecular defects driving relapse and drug resistance are unknown. Methods We performed Illumina or Complete Genomics whole genome sequencing of 23 paired diagnostic and relapsed neuroblastomas, and corresponding normal lymphocyte DNA, to define genetic alterations associated with relapse. A panel of 18 neuroblastoma cell lines was analyzed for the presence of RAS-MAPK mutations and sensitivity to small molecule inhibitors of this pathway. Results Neuroblastomas that relapsed after chemotherapy showed dramatic clonal evolution, with only 33% of primary tumor mutations also detected at relapse. In 21 out of 23 patients, more somatic coding mutations were observed at relapse (median: 29 unique to relapse, range: 4-129). Unbiased pathway analysis of the somatic mutations detected in the relapse tissues identified a strong enrichment in genes associated with RAS-MAPK signaling (p = 6.1×10−7). 18 of the 23 cases (78%) showed somatic mutations (N = 15) or structural alterations (N = 3) predicted to activate the MAPK pathway, and these were mutually exclusive: ALK (N = 10), NRAS (N = 1), KRAS (N = 1), HRAS (N = 1), BRAF (N = 1), PTPN11 (N = 1), FGRF1 (N = 1) and NF1 (N = 2). These RAS-MAPK mutations were clonally enriched at relapse and exist within clonal or major subclonal tumor populations. Seven of these RAS-MAPK mutations were detected only in the relapse tumor by whole genome sequencing (∼50X coverage), and only 2 of these 7 mutations were detectable in the primary tumor with targeted detection methods (104-105X coverage). Similar MAPK pathway mutations were detected in 11 of 18 human neuroblastoma-derived cell lines, and these lesions are predicted to be sensitive to small molecule inhibition of MEK in vitro (p<0.001) and in vivo (p<0.05). Conclusions In this study of 23 neuroblastoma cases selected based solely on having diagnostic-relapse specimens available for analysis, MAPK pathway mutations were highly enriched in the relapsed genomes, providing a potential biomarker for new therapeutic approaches to chemotherapy refractory disease. The fact that several ALK-RAS-MAPK mutations were found in the relapse but not in the corresponding primary tumors favors a model in which rare subclones with secondary driver mutations expand over time. However, it remains to be determined whether these mutations occurred de novo after treatment, were present in rare subclones below detection limits, or were undetectable due to spatial heterogeneity of the primary tumor, which will impact the clinical utility of targeted sequencing at diagnosis. Our study provides strong rationale for performing biopsies on relapse neuroblastoma tumors in order to comprehensively characterize the molecular lesions that underlie treatment-refractory disease, determine their prognostic relevance, and guide treatment decisions for patients. Citation Format: Derek A. Oldridge, Thomas F. Eleveld, Virginie Bernard, Jan Koster, Leo C. Daage, Sharon J. Diskin, Linda Schild, Nadia B. Bentahar, Angela Bellini, Mathieu Chicard, Eve Lapouble, Valérie Combaret, Patricia Legoix-Né, Jean Michon, Trevor J. Pugh, Lori S. Hart, JulieAnn Rader, Edward F. Attiyeh, Jun S. Wei, Shile Zhang, Arlene Naranjo, Julie M. Gastier-Foster, Michael D. Hogarty, Malcolm A. Smith, Jaime G. Auvil, Thomas B. K. Watkins, Danny A. Zwijnenburg, Marli E. Ebus, Peter van Sluis, Anne Hakkert, Esther van Wezel, C. Ellen van der Schoot, Ellen M. Westerhout, Johannes H. Schulte, Godelieve A. Tytgat, M. Emmy M. Dolman, Isabelle Janoueix-Lerosey, Daniela S. Gerhard, Huib N. Caron, Olivier Delattre, Javed Khan, Rogier Versteeg, Gudrun Schleiermacher, John M. Maris, Jan J. Molenaar. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2980. doi:10.1158/1538-7445.AM2015-2980
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) | 0,002 | 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 ».