Abstract 4350: Clonal selection and parallel evolution during leptomeningeal dissemination of human and mouse medulloblastoma result in bicompartmental disease
Notice bibliographique
Résumé
Abstract Medulloblastoma metastasizes through the CSF in the leptomeningeal space to cover the brain and spinal cord. Mechanisms driving metastasis are currently unknown. It had been assumed that the primary tumor and its metastases share very similar biology. The Sleeping Beauty (SB) system is a novel functional genomics tool for cancer gene discovery. Ptch +/− mice develop localized medulloblastoma in 15% of cases, while ≈100% of Math1-SB11, SB transposon donor, Ptch +/− mice develop metastatic medulloblastoma. We sequenced over 158,000 insertion sites (Roche 454) from a series of >140 SB-induced primary medulloblastomas, as well as matched spinal and frontal lobe leptomeningeal metastases. Statistical analysis identified 359 commonly inserted genes (CIGs) in the primary tumors and 285 CIGs in the leptomeningeal metastases. Although primary tumors and their metastases always demonstrate a common transformed ancestor through sharing of identical clonal insertion sites, less than 10% of CIGs were found in both primary tumor and matched metastases. Matched spinal and frontal lobe metastases shared identical clonal insertions that were very highly subclonal in the primary tumor, suggesting that leptomeningeal dissemination arises only once, or from a single small subclonal population in the primary tumor. These data support the clonal selection model of metastasis, and suggest that MET-CIG insertions are acting as metastasis virulence genes. Similarity between metastases supports a model in which medulloblastoma is a bicompartmental disease (primary vs. metastases) that arises through parallel evolution in the two compartments. We validated our mouse model through copy number profiling of three matched trios of human medullolblastoma (primary and two metastases). In each case we demonstrate highly clonal regions of chromosomal gain/loss that are present in both metastatic samples, but are not apparent in the matched primary tumor. Similarly, profiling of promotor CpG island methylation in human primary medulloblastomas and matched metastases shows that within a given child the metastases are very similar to each other, but distinct from the primary tumor. PCR amplification was used to demonstrate a clonal 179 Kb deletion in a pair of human metastases, which was present in an extremely small subclone of the primary tumor, strongly supporting the clonal selection model during dissemination of human medulloblastoma. Our results support a model in which individual medulloblastomas metastases are similar to each other, but distinct from the primary tumor. This ‘bicompartmental model’ suggests a proximate reason for failure of current therapies, and that future clinical trials may need to address each compartment individually. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4350.
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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 | 0,000 |
| 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) | 0,001 | 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 ».