Abstract 4126: Identifying novel tumor modifier genes involved in gliomagenesis using retroviral gene-trapping mutagenesis screens
Notice bibliographique
Résumé
Abstract Glioblastoma multiforme (GBMs) are the most common and lethal of all gliomas, with an average survival of ∼ 12-16 months. Several gain- and loss-of-function genetic alterations have been implicated in gliomagenesis leading to GBM formation, however many more genetic alterations exist, as evidenced by recent reports from The Cancer Genome Atlas (TCGA) project on human GBMs. Well-characterized mouse models, especially those that progressively develop gliomas, also, offer an opportunity to discover novel glioma relevant genetic alterations, using viral and non-viral random mutagenesis strategies. Using gene-trap strategies in our spontaneous transgenic mouse RasB8 glioma model, which expresses V12H-Ras under the control of the astrocyte tissue specific human promoter GFAP, we identified GATA6, a member of the GATA family of transcription factors, as a novel tumour suppressor gene (TSG) involved in progression of human GBMs and GATA4, a close family member of GATA6, to also function as a TSG involved in initiation of gliomagenesis. We now generated novel gain of function and loss of function gene-traps and transduced non-transformed but genetically susceptible primary murine astrocytes harboring either activated V12H-Ras, or loss of the tumour suppressors, p53, Ink4a/Arf, Pten−/− and over-expression of the human EGFRvIII mutant. Pending verification in our mouse models and human specimens we hypothesized that that trapped clones from V12H-Ras, p53 null and Ink4a/ARF null astrocytes would reveal progression factors, as these genetic alterations are associated with human low grade gliomas and occur early on in GBM formation. In contrast, trapped clones from astrocytes with EGFRvIII or Pten−/−, already demonstrated to promote progression, would likely lead to the discovery of initiation factors. Several gene-trapped clones led to transformation as measured by soft agar assays in initial screens using astrocytes with activated V12H-Ras. By means of inverse PCR we identified gene-trap insertion sites in introns of RapGap1, Ikkβ, Socs6, and Pink1 leading to loss of function. Of great interest was PTEN induced Kinase 1, PINK1, a mitochondrial serine/threonine kinase that is frequently mutated in patients in Parkinson disease while its link to cancer and GBM is poorly characterized. Initial screening in GBMs reveals reduced expression of PINK1 protein compared to normal human astrocyte controls. Pink1 gene-trap clones also exhibited increased proliferation and increased transformation compared to empty vector controls providing initial evidence that mouse and human PINK1 may have tumour suppressive properties, with current validation in progress. Gene-trapping strategies in robust animal models provide an invaluable tool that complement large scale cancer genome sequencing projects in identification of relevant driver GBM modifier genes in random non-biased manner. 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 4126.
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) | 0,001 | 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 ».