Abstract 198: Two novel insertion polymorphisms of the BRM gene are associated with loss of BRM expression and lung cancer risk
Notice bibliographique
Résumé
Abstract BACKGROUND: BRM, a catalytic subunit of the SWI/SNF chromatin remodeling complex, regulates expression/function of key signal transduction pathways with anticancer functions. In 15-25% of lung cancers, BRM protein expression is lacking. When BRM null mice (who display distinct cell cycle abnormalities) are exposed to carcinogens, they develop 10-fold more tumors then control mice. BRM silencing does not appear to be driven by mutational changes. We hypothesized that BRM silencing may be related to sequence variants in the BRM promoter region. METHODS: We compared novel BRM promoter polymorphisms to BRM protein expression in cancer cell lines and tumors of lung cancer patients. We then performed a case-control analysis of these polymorphisms with lung cancer risk. RESULTS: Sequencing of human cancer cell lines identified a 7-bp (rs34480940; located −741 from transcription start site) and 6-bp (rs3832613; located −1321) BRM insertion polymorphisms. In Caucasians, minor allele frequencies (MAF) of 45% were found for both polymorphisms. Cancer cell lines were evaluated for BRM protein expression (Western blot). Twelve BRM staining (BRM-positive) and twelve non-staining (BRM-negative) cancer cell lines were genotyped. In the BRM-negative cell lines, 11/12 cell lines were homozygous variant for at least one of the two BRM promoter polymorphisms (5/12 were double homozygous; 6/12 were homozygous for one polymorphism). In contrast, the BRM-positive cell lines yielded a good mix of genotypes for both polymorphisms. In lung cancer tissues, all ten BRM-negative samples carried at least one homozygous variant (eight were double homozygous variant, while two were homozygous for one polymorphism). In contrast, genotyping of normal adjacent tissue of twelve BRM-positive samples yielded population-normal MAFs of 42% for BRM −741 and 46% for BRM −1321. Tumour-normal tissue genotyping concordance rate was 86%. In the case-control analysis, 484 ever-smoker lung cancer cases were compared to 715 age and gender frequency-matched ever-smoker controls. Compared with a wildtype reference, carrying one homozygous variant was associated with an adjusted odds ratio (aOR) of 1.40 (95%CI:0.95-2.05; p=0.09); carrying two homozygous variants was associated with aOR=2.19 (1.40-3.43; p=0.0006), after adjusting for age, gender, and smoking variables. CONCLUSIONS: Homozygous variants of two novel BRM promoter polymorphisms are tightly associated with loss of BRM expression in lung cancer tissues and cancer cell lines. These homozygous variants are also associated with lung cancer risk in ever-smokers. Since epigenetic silencing of BRM can be reversed by various compounds (e.g. HDAC inhibitors, novel compounds from screening libraries), reversing BRM silencing could be developed as part of a chemoprevention strategy in smokers who carry the homozygous variants of these two BRM promoter polymorphisms. 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 198.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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 | 0,000 | 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) | 0,000 | 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 tête enseignante, 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 ».