Abstract B12: H3-K27M is a negative prognostic marker in high- and low-grade pediatric thalamic glioma
Notice bibliographique
Résumé
Abstract Pediatric gliomas are the most commonly diagnosed brain cancer in children, accounting for approximately 50% of all cases. Work by our group and others has revealed recurrent histone mutations in diffuse intrinsic pontine glioma (DIPG), astrocytomas that arise in the brainstem of children and boast a dismal median survival of less than one year. In ~70% of DIPG, a mutation in histone variant H3.3 or H3.1 at position 27 leads to substitution of a lysine by a methionine (K27M). When correlated to clinical data, patients harbouring H3-K27M mutations showed a worse prognosis in comparison to patients wild type for H3 (H3-WT), regardless of their histologic grade. Investigation into H3-K27M prevalence in pediatric gliomas revealed that they were not exclusively observed in the brainstem, but rather, in additional midline structures such as the thalamus. However, the clinical relevance of H3-K27M in other midline tumours has not yet been investigated. We hypothesized that H3-K27M would represent a negative prognostic marker in pediatric thalamic gliomas. We searched the Hospital for Sick Children's tumour archives and obtained 86 radiologically confirmed cases of pre-treatment thalamic glioma. The cohort contained 46 male and 40 female patients with a combined median age of diagnosis and survival of 9.04 and 3.88 years, respectively. Of the 86 samples analyzed, 53 were histologically reviewed as low grade malignancies while 33 appeared high grade. Median survival for patients with high grade thalamic gliomas was 1.02 years vs 8.71 years for low grade thalamic glioma patients. Six (11.3%) low grade and 17 (51.5%) high grade gliomas tested positive for the H3-K27M mutation. Patients were clinically annotated for treatment, extent of resection, age of diagnosis and outcome (median follow-up of 10.3 years) and were used to determine the prognostic implications of H3-K27M. Kaplan-Meier survival analysis revealed significantly worse overall survival of thalamic glioma patients harbouring the H3-K27M mutation versus wild type samples (log rank p<0.001) with a median survival of 0.91 vs. 7.23 years for H3-K27M vs. WT thalamic gliomas, respectively. When separated by histologic grade, H3-K27M status remained a prognostic marker in each histologic grade (p=0.021 and p<0.001 for high and low grade tumours, respectively). Interestingly, H3-K27M low grade astrocytomas did worse than H3-WT low grades (p<0.001), yet better than H3-K27M high grades (p<0.001). This suggests the potential for clinical sub-grouping of thalamic tumours based on histologic grade and H3-K27M status. Multivariate analysis including extent of resection, treatment, age of diagnosis, sex, histologic grade and mutation status demonstrated H3-K27M status to be the most significant predictor of overall survival with a hazard ratio of 10.89 (95% confidence intervals 2.86-41.47, p<0.001). Additionally, histologic grade was the only other significant predictor of outcome with a hazard ratio of 5.53 (95% confidence interval of 2.20-13.91, p<0.001). These findings provide the first evidence that H3-K27M is a negative prognostic indicator for pediatric thalamic glioma. Further, the survival difference between H3-K27M mutant low grade and high grade astrocytoma suggests differing biology and a role for “second hits” in dictating the aggressiveness of these tumours. Importantly, it supports prognostic subgrouping based on mutation status and histologic grade. Citation Format: Scott Ryall, Pawel Buczkowicz, Anthony Arnoldo, Rahul Krishnatry, Matthew Mistry, Joshua Rubin, Paul Steinbok, Uri Tabori, Cynthia Hawkins. H3-K27M is a negative prognostic marker in high- and low-grade pediatric thalamic glioma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B12.
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 | 0,000 | 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 | 0,000 |
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 ».