Abstract LB-346: A novel lung tumor suppressor implicated in somatic and familial cancers
Notice bibliographique
Résumé
Abstract Background: Lung cancer (LC) is the most common cause of cancer death worldwide. Previous familial linkage studies have identified a tumor suppressor locus on 6q23-25. However, no single gene has yet been implicated within this 30 Mb region. Discovering the genetic and epigenetic events that affect LC risk and development will lead to better methods for risk assessment, early detection and treatment. Methods: Genome-wide genes disrupted by two-hit inactivation were identified by combining gene dosage, DNA methylation, and gene expression assays for a group of lung adenocarcinomas (AC) and adjacent non-malignant tissues. Gene expression, DNA hypermethylation and/or copy number aberrations were validated in data from AC, squamous cell carcinoma (SqCC), and pre-malignant lesions by querying other cohorts using gene-specific and whole-genome approaches. The role of DNA methylation in gene silencing was assessed using inhibition of DNMT by 5′-azacytidine. The association of allelic variants with LC risk was investigated in 193 familial LC cases and 213 controls collected by the Genetic Epidemiology of Lung Cancer Consortium (GELCC) using a Cochrane-Armitage trend test. The association of gene expression with prognosis was performed on public data using a Mantel-Cox log test. Stable mRNA knock-downs were generated using lentiviral delivery of a gene-specific shRNA, and apoptotic cells were counted using Annexin5/propidium iodide staining. Results: Integration of AC gene dosage, DNA methylation and mRNA expression showed EYA4 to be frequently affected by two-hits and significantly down-regulated. Quantitative PCR techniques confirmed that EYA4 was hypermethylated (46%) and down-regulated (72%), validating our microarray results. A direct link between EYA4 methylation and expression was verified by restoration of expression after 5′-azacytidine treatment in methylated cell lines. Congruent with EYA family member function, in vitro assays revealed that EYA4 knock-down cells displayed a decrease in the number of apoptotic cells - a hallmark of cancer. Further investigations led to the discovery of frequent EYA4 disruption in SqCC and pre-neoplastic tissue. The GELCC dataset was examined to assess EYA4 allelotype association with familial risk. Doing so revealed that numerous EYA4 variants are associated with increased risk. Finally, the association of EYA4 expression with survival was investigated along with other somatically altered genes at 6q23-25. Of these genes, low EYA4 expression was found to be the most significantly associated with poor prognosis. Conclusions: EYA4 is a frequently disrupted gene that maps to a locus previously associated with cancer risk. It is implicated in somatic as well as familial cancers, and is likely a tumor suppressor gene with apoptotic functions. The direct association of EYA4 with risk and survival underscores its relevance on a clinical level. 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 LB-346.
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 | 0,000 |
| 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 ».