MP61-01 FUNCTIONAL ROLE OF THE KALLIKREIN 6 REGION OF THE KALLIKREIN LOCUS IN GENETIC PREDISPOSITION FOR AGGRESSIVE (GLEASON ≥8) PROSTATE CANCER: FINE-MAPPING AND METHYLATION STUDY IN A CANADIAN COHORT AND THE SWISS ARM OF THE EUROPEAN RANDOMIZED STUDY FOR PROSTATE CANCER SCREENING
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Résumé
You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2015MP61-01 FUNCTIONAL ROLE OF THE KALLIKREIN 6 REGION OF THE KALLIKREIN LOCUS IN GENETIC PREDISPOSITION FOR AGGRESSIVE (GLEASON ≥8) PROSTATE CANCER: FINE-MAPPING AND METHYLATION STUDY IN A CANADIAN COHORT AND THE SWISS ARM OF THE EUROPEAN RANDOMIZED STUDY FOR PROSTATE CANCER SCREENING Laurent Briollais, Hilmi Ozcelik, Maciej Kwiatkowski, Jingxiong Xu, Sevtap Savas, Ekaterina Olkhov-Mitsel, Franz Recker, Cynthia Kuk, Sally Hanna, Neil E Fleshner, Tristan Juvet, Matt Friedlander, Hong Li, Karen Chadwick, John Trachtenberg, Ants Toi, Theodorus H van der Kwast, Eleftherios P Diamandis, Bharati Bapat, and Alexandre R. Zlotta Laurent BriollaisLaurent Briollais More articles by this author , Hilmi OzcelikHilmi Ozcelik More articles by this author , Maciej KwiatkowskiMaciej Kwiatkowski More articles by this author , Jingxiong XuJingxiong Xu More articles by this author , Sevtap SavasSevtap Savas More articles by this author , Ekaterina Olkhov-MitselEkaterina Olkhov-Mitsel More articles by this author , Franz ReckerFranz Recker More articles by this author , Cynthia KukCynthia Kuk More articles by this author , Sally HannaSally Hanna More articles by this author , Neil E FleshnerNeil E Fleshner More articles by this author , Tristan JuvetTristan Juvet More articles by this author , Matt FriedlanderMatt Friedlander More articles by this author , Hong LiHong Li More articles by this author , Karen ChadwickKaren Chadwick More articles by this author , John TrachtenbergJohn Trachtenberg More articles by this author , Ants ToiAnts Toi More articles by this author , Theodorus H van der KwastTheodorus H van der Kwast More articles by this author , Eleftherios P DiamandisEleftherios P Diamandis More articles by this author , Bharati BapatBharati Bapat More articles by this author , and Alexandre R. ZlottaAlexandre R. Zlotta More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2182AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Novel prostate cancer (PCa) markers that can identify individuals at increased risk of harboring an aggressive form of the disease are needed. We previously demonstrated that a novel locus in the KLK6 region was strongly associated with PCa aggressiveness. We further explored the functional role of this KLK6 locus. METHODS 380 PCa cases were accrued from the Swiss arm of the European Randomized Study of Screening for PCa and 540 from Toronto. We genotyped (Illumina platform) 123 tag SNPs selected from the entire KLK region using a stringent definition for PCa aggressiveness (GS<8 vs ≥8). A total of 880 SNPs imputed from the 1,000 genomes data and 47 SNPs imputed from Hapmap provided a dense map of the KLK region. We quantified the KLK6 tissue methylation levels using the MethyLight assay (percent DNA methylation, PMR) in 115 pairs of PCa and normal tissue samples (Toronto). The methylation data for KLK6 were analyzed as PMR score in the tumor tissue – PMR score in the normal tissue (defined as PMRdiff). A PMR score was calculated for the KLK6 gene locus by dividing the KLK6 gene:Alu-C4 ratio of a sample by the KLK6 gene:Alu-C4 ratio of commercially available fully methylated DNA and multiplying by 100. RESULTS Five SNPs in very strong linkage disequilibrium (LD) in the KLK6 gene (rs113640578, rs79324425, rs11666929, rs28384475, rs3810287) were highly associated with PCa aggressiveness when discriminating between GS<8 vs ≥8 in the Swiss cohort (p=9.5x10-5) and the Toronto cohort (6.5x10-3 to 1x10-2). Using bioinformatics, two additional SNPs (rs78353057 and rs201147694) were in strong linkage equilibrium with these five SNPs. Haploreg analyses showed that all 7 SNPs may have regulatory functions; rs11666929 was in a RAD21 protein binding site; 3 SNPs were in DNAse sensitive regions and 4 at potential histone modification sites. Based on the covariance analysis of the GS, we found a significant interaction between SNP rs113640578 in KLK6 and PMRdiff, (P=0.048) at the tissue level supporting that the increase of GS due to KLK6 methylation was significantly higher in individuals carrying the rare allele of rs113640578 compared to those having the common allele. CONCLUSIONS Our fine-mapping study has identified a novel locus in the KLK6 region strongly associated with PCa aggressiveness and functional results suggest that this locus resides within the transcription factor binding sites of the gene. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e746-e747 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Laurent Briollais More articles by this author Hilmi Ozcelik More articles by this author Maciej Kwiatkowski More articles by this author Jingxiong Xu More articles by this author Sevtap Savas More articles by this author Ekaterina Olkhov-Mitsel More articles by this author Franz Recker More articles by this author Cynthia Kuk More articles by this author Sally Hanna More articles by this author Neil E Fleshner More articles by this author Tristan Juvet More articles by this author Matt Friedlander More articles by this author Hong Li More articles by this author Karen Chadwick More articles by this author John Trachtenberg More articles by this author Ants Toi More articles by this author Theodorus H van der Kwast More articles by this author Eleftherios P Diamandis More articles by this author Bharati Bapat More articles by this author Alexandre R. Zlotta More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
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 | 0,001 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,012 | 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 ».