MP68-06 TISSUE-BASED DNA METHYLATION PROFILING ESTABLISHES A NOVEL PANEL OF BIOMARKERS FOR DISCRIMINATION OF HIGH-GRADE VERSUS LOW-GRADE BLADDER CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research IV1 Apr 2015MP68-06 TISSUE-BASED DNA METHYLATION PROFILING ESTABLISHES A NOVEL PANEL OF BIOMARKERS FOR DISCRIMINATION OF HIGH-GRADE VERSUS LOW-GRADE BLADDER CANCER Andrea Savio, Ekaterina Olkhov-Mitsel, Ken Kron, Thomas Hermanns, Bas van Rhijn, Alexandre Zlotta, Theodorus van der Kwast, and Bharati Bapat Andrea SavioAndrea Savio More articles by this author , Ekaterina Olkhov-MitselEkaterina Olkhov-Mitsel More articles by this author , Ken KronKen Kron More articles by this author , Thomas HermannsThomas Hermanns More articles by this author , Bas van RhijnBas van Rhijn More articles by this author , Alexandre ZlottaAlexandre Zlotta More articles by this author , Theodorus van der KwastTheodorus van der Kwast More articles by this author , and Bharati BapatBharati Bapat More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2468AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Epigenetic changes, including promoter CpG island hypermethylation, occur frequently in bladder cancer (BC) and may be exploited as a means for BC detection and distinction between high-grade (HG) and low-grade (LG) disease. METHODS To determine epigenetic differences between LG and HG BC we performed genome-wide methylation analysis with Agilent Human CpG Island Microarrays on a panel of fresh frozen BC tissue samples. Using Linear Models for Microarray Data (LIMMA) and local-pooled-error (LPE) approaches and unsupervised hierarchical clustering we identified 990 probes comprising a 32-gene panel that completely distinguished LG from HG BC based on methylation status. We selected five representative differentially methylated genes (DMGs) from our 32-gene panel for methylation validation by real-time PCR-based MethyLight in a series of 40 LG cases age- and sex-matched to 40 HG cases. RESULTS Among the DMGs tested, including EOMES, GP5, PAX6, TCF4, and ZSCAN12, we identified that EOMES, GP5, and ZSCAN12 methylation significantly differs between normal, LG, and HG disease. GP5 and ZSCAN12, two novel methylated genes in BC, are significantly hypermethylated in HG versus LG BC (p=0.006 and 0.028, respectively). Pathway enrichment analysis and functional annotation determined the most frequently methylated pathways in HG BC were enriched for anterior/posterior pattern specification, embryonic skeletal system development, and neuron fate commitment. The molecular functions of the most enriched genes were involved in DNA binding and transcription factor activity. CONCLUSIONS These results indicate the ability to distinguish normal tissue from cancer, as well as LG from HG tumours, and reveal important pathways dysregulated in HG BC. Ultimately, the creation of a methylation panel able to distinguish between disease phenotypes will improve disease management and patient outcomes. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e860 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrea Savio More articles by this author Ekaterina Olkhov-Mitsel More articles by this author Ken Kron More articles by this author Thomas Hermanns More articles by this author Bas van Rhijn More articles by this author Alexandre Zlotta More articles by this author Theodorus van der Kwast More articles by this author Bharati Bapat More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...