Abstract B21: Epigenetic and post-transcriptional regulation of the kallikrein gene family as a novel panel of prostate cancer biomarkers
Notice bibliographique
Résumé
Abstract Prostate cancer (PCa), the most commonly diagnosed cancer in North American men, is currently detected using a serum test for prostate-specific antigen (PSA), a protein encoded by kallikrein 3 (KLK3). However, PSA testing has limited sensitivity and specificity leading to over-diagnosis of PCa. Therefore, improved biomarkers are urgently needed to identify aggressive vs. indolent PCa. Other members of the 15-member KLK gene family, which encode for serine proteases, are likely candidates since their expression is altered in PCa. Emerging evidence has shown that epigenetic mechanisms such as DNA methylation and aberrant microRNA (miRNA) expression may regulate KLK expression in carcinogenesis. Importantly, these marks are potentially promising biomarkers since they can be detected in tissue and serum samples of PCa patients. Studies to date have not examined how DNA methylation and miRNA regulation mechanisms cooperate to influence KLK regulation. Using genome-wide CpG island DNA methylation profiling, we identified tumor-specific hypermethylation of KLK6 and KLK10 genes in PCa which we validated using methylation specific quantitative real-time PCR (MethyLight). We demonstrated that KLK10 DNA methylation was significantly associated with pathological stage and ERG oncogene expression status in 2 independent cohorts of PCa patients (Cohort I, n=150 and II, n=124, P-value =0.007, 0.031, P-value =0.001, P<0.001, respectively). Further, in cohort II, low KLK10 DNA methylation was associated with biochemical recurrence in univariate and multivariate analyses (P-values=0.046, 0.028, respectively, HR=2.11, 95% CI: 1.10-4.02). A similar trend for KLK6 DNA methylation was observed. The results suggest that KLK6 and KLK10 DNA methylation distinguishes organ confined from locally invasive PCa and may have prognostic value. To better understand the regulation of this protease family and potentially PCa pathogenesis, we have performed in silico analysis to identify a panel of miRNAs implicated in KLK regulation. Notably, we found mir-137 was predicted to target KLK10 and was hypomethylated by genome-wide methylation array profiling. Among the 21 CpG island microarray probes representing the mir-137 genomic region, 3 were significantly differentially methylated in high grade vs. low grade PCas and 5 were significantly differentially methylated between ERG positive and negative cases (P-values<0.05). We then measured mir-137 expression in PCa patients from cohort I using quantitative real time PCR and determined relative quantities of miRNA using 2-ΔCt method after normalization to U6 snRNA. The expression of mir-137 was 37% higher in PCa tissue vs. normal (P-value=0.28). Further, the proportion of cases with high mir-137 expression, based on a third quartile threshold, were significantly different between Gleason Score (GS) ≥8 vs. GS ≤7 and ERG positive vs. negative expression status (P-values=0.035, 0.013, respectively). These findings highlight the complexity of epigenetic regulatory systems and pave the way for further investigation of miRNA regulation of the KLK gene family. The association of KLK10 methylation and mir-137 profiles with ERG expression status further characterizes molecular subtypes of PCa, which will allow for potentially establishing a diagnostic and/or prognostic model of clinical significance for PCa. Citation Format: Ekaterina Olkhov-Mitsel, Theodorus Van der Kwast, Ken Kron, Hilmi Ozcelik, Laurent Briollais, Neil Fleshner, Eleftherios Diamandis, Alexandre Zlotta, Bharati Bapat. Epigenetic and post-transcriptional regulation of the kallikrein gene family as a novel panel of prostate cancer biomarkers. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B21.
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 ».