OS5.1 Molecular subgroups of low- and high-grade gliomas diagnosed in the first year of life
Notice bibliographique
Résumé
CNS tumours are the most common malignancies in infants. The majority of tumours diagnosed in the first year of life are gliomas. Though considered benign, low-grade gliomas (LGG) diagnosed in infancy have a worse outcome, whereas high-grade gliomas (HGG) have a better outcome than their counterparts in older children. We sought to determine the genetic drivers and clinical factors that impact outcome of this understudied patient population. Multi-institutional retrospective study of patients diagnosed with gliomas (WHO I-IV) in the first year of life. Clinical information and samples were collected for 171 patients diagnosed between 1985 and 2017. Histopathology was centrally reviewed and whenever sufficient tissue was available DNA and RNA extracted for molecular studies. Tier 1 of molecular studies consisted of clinically available tools, including a Nanostring panel detecting known glioma-associated fusions and ddPCR for BRAFV600E and H3K27M. Selected negative cases were then further profiled in tier 2 by RNA sequencing, SNP array and/or methylation array. Novel oncofusions were further validated. Ten-year overall survival for LGG and HGG in the entire cohort was 77% and 35%, respectively. Midline diencephalic tumours were predominantly low-grade (optic pathway gliomas, OPG), comprising 98% of all diencephalic tumours and 47% of all LGG. Molecular analysis of OPG revealed high frequency of BRAF alterations, with 44% carrying a BRAFV600E mutation and 36% a BRAF-KIAA1549 fusion. OPG were associated with a markedly worse outcome when compared with LGGs at other locations (10-year overall survival of 63% vs 92%), suggesting that these patients respond poorly to conventional treatment and should be prioritized for targeted therapies. Strikingly, hemispheric tumours (35% of all LGG and 82.4% of all LGG and HGG, respectively) were found to have recurrent alterations shared between LGG and HGG, most notably novel gene fusions involving the ALK oncogene. Additionally, NTRK, FGFR, MET and novel fusions involving ROS1 were found predominantly in hemispheric tumours, particularly in HGG. iNHA cells transduced with CCDC88A-ALK fusion and implanted intracranially in NSG mice were tumorigenic in vivo with a short latency and 100% penetrance. Gliomas in infants have a distinct molecular profile and clinical course. Whereas diencephalic tumours are predominantly low-grade and driven by BRAF alterations, recurrent alterations involving NTRK/ALK/ROS1, FGFR and MET are found in HGG and a subset of these alterations are shared with LGG hemispheric tumours. Our study characterizes a critically understudied patient population and reveals a high frequency of targetable alterations, supporting routine molecular studies and the use of targeted inhibitors in future clinical trials.
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 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 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 | 0,000 |
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 ».