Abstract 4872: ICGC PedBrain Tumor - Next-generation sequencing identifies novel subgroup-specific mutations and copy number aberrations in medulloblastoma
Notice bibliographique
Résumé
Abstract Introduction: The International Cancer Genome Consortium (ICGC) is a worldwide network aiming to provide comprehensive molecular genetic profiles of 50 clinically and societally important tumors. A major focus of the ICGC PedBrain Tumor project is medulloblastoma (MB) - the most common malignant brain tumor in childhood. Importantly, recent work has shown that MB is not a single disease, but is in fact comprised of 4 distinct molecular subgroups (WNT, SHH, Group 3, Group 4). Using an integrative next-generation sequencing-based approach, we have investigated tumorigenic events underlying medulloblastoma, with the aim of identifying novel diagnostic or prognostic markers, and therapeutic targets. Methods: The whole genome of 50 tumor-normal DNA pairs, plus the whole exome or 2,500 target genes in a further 100 sample pairs from different histological and transcriptomic subgroups, was sequenced on an Illumina HiSeq platform. Sequencing-based high-resolution copy-number data was also generated for all cases. Results: Overall, a smaller number of non-synonymous somatic mutations was seen than in most adult malignancies. The number of somatic changes also clearly showed a positive correlation with patient age, suggesting either longer-term selection for more weakly transforming alterations, or the acquisition of additional passenger mutations in tumors which grew over a longer period. Whilst some point mutations and small InDels affected known MB or cancer-related genes (e.g. CTNNB1, PTCH1, MLL2), the vast majority were in genes which have not previously been implicated in medulloblastoma. Furthermore, even the most recurrently altered genes were mutated in <20% of samples overall, although several showed a clear enrichment in distinct subgroups. Pathway analysis revealed chromatin modification as one of the most frequently altered cellular processes, with hits in multiple pathway members. Novel copy-number alterations were also identified. For example, a pattern of catastrophic chromosome shattering (‘chromothripsis’) was observed almost exclusively in the SHH tumor subgroup. Conclusion: Next-generation sequencing of this large tumor cohort has provided a number of new insights into this deadly pediatric tumor. The overriding pattern is one of enormous heterogeneity, but integration with molecular subgrouping shows clear enrichment of certain alterations. This first stage of the ICGC PedBrain project has demonstrated the power of next-gen sequencing approaches to reveal significant new insights, providing a number of novel targets for potential therapeutic intervention. It also, however, indicates the importance of personalised approaches to treatment optimisation, and shows the scale of the coming challenge in terms of functionally validating the huge number of novel mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4872. doi:1538-7445.AM2012-4872
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 | 0,001 | 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 | 0,001 | 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 ».