Frequent mutations in acetylation and ubiquitination sites suggest novel driver mechanisms of cancer
Notice bibliographique
Résumé
BACKGROUND: Discovery of cancer drivers is a major goal of cancer research. Driver genes and pathways are often predicted using mutation frequency, assuming that statistically significant recurrence of specific somatic mutations across independent samples indicates their importance in cancer. However, many mutations, including known cancer drivers, are not observed at high frequency. Fortunately, abundant information is available about functional "active sites" in proteins that can be integrated with mutations to predict cancer driver genes, even based on low frequency mutations. Further, considering active site information predicts detailed biochemical mechanisms impacted by the mutations. Post-translational modifications (PTMs) are active sites that are regulatory switches in proteins and pathways. We analyzed acetylation and ubiquitination, two important PTM types often involved in chromatin organization and protein degradation, to find proteins that are significantly affected by tumor somatic mutations. METHODS: We performed computational analyses of acetylation and ubiquitination sites in a pan-cancer dataset of 3200 tumor samples from The Cancer Genome Atlas (TCGA). These analyses were targeted at different levels of biological organization including individual genes, pathway annotated gene sets, and protein-protein interaction networks. RESULTS: Acetylation and ubiquitination site mutations are enriched in cancer with significantly stronger evolutionary conservation and accumulation in protein domains. Gene-focused analysis with the ActiveDriver method reveals significant co-occurrences of acetylation and ubiquitination PTMs and mutation hotspots in known oncoproteins (TP53, AKT1, IDH1) and highlights candidate cancer driver genes with PTM-related mechanisms (e.g. several histone proteins and the splicing factor SF3B1). Pathway analysis shows that PTM mutations in acetylation and ubiquitination sites accumulate in cancer-related processes such as cell cycle, apoptosis, chromatin regulation, and metabolism. Integrated mutation analysis of clinical information and protein interaction networks suggests that many PTM-specific mutations associate with decreased patient survival. CONCLUSIONS: Mutation analysis of acetylation and ubiquitination PTM sites reveals their importance in cancer. As PTM networks are increasingly mapped and related enzymes are often druggable, deeper investigation of specific associated mutations may lead to the discovery of treatment-relevant cellular mechanisms.
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 ».