MP31-15 GENE EXPRESSION PROFILING REVEALS MOLECULAR SUBTYPES OF BENIGN PROSTATIC HYPERPLASIA

Abstract

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research1 Apr 2015MP31-15 GENE EXPRESSION PROFILING REVEALS MOLECULAR SUBTYPES OF BENIGN PROSTATIC HYPERPLASIA Keyan Salari, Seth Bechis, Rongbin Ge, Jian Hong, Aleksander Otsetov, Zongwei Wang, Shahin Tabatabaei, and Aria Olumi Keyan SalariKeyan Salari More articles by this author , Seth BechisSeth Bechis More articles by this author , Rongbin GeRongbin Ge More articles by this author , Jian HongJian Hong More articles by this author , Aleksander OtsetovAleksander Otsetov More articles by this author , Zongwei WangZongwei Wang More articles by this author , Shahin TabatabaeiShahin Tabatabaei More articles by this author , and Aria OlumiAria Olumi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1370AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Benign prostatic hyperplasia (BPH) affects over 80% of men by age 70 and poses a substantial burden on healthcare. At least 25-30% of men do not respond to 5-alpha reductase (5-AR) inhibitors, raising the hypothesis that there may be molecular heterogeneity in BPH underlying this variability in clinical response. In previous work, we showed that some men carry epigenetic modifications via methylation of the 5-AR promoter region that modulate gene expression and protein levels, thereby suggesting a possible mechanism of resistance to 5-AR inhibitors. In this study, we performed genome-wide gene expression profiling of prostatic tissue from patients with BPH to identify molecular subtypes of the disease with potential clinical relevance. METHODS Prostatic tissue specimens were obtained at the time of surgery from 22 patients with symptomatic BPH undergoing prostate debulking surgery. Each patient's tissue was analyzed for the presence of 5-AR type 2 protein expression by immunohistochemistry and 5-AR2 gene promoter methylation status by PCR-based methylation analysis. Total RNA was extracted from each specimen for gene expression profiling. Whole-genome gene expression profiling was performed using Illumina Human HT-12 v4 BeadChip Arrays. Gene expression microarray data was analyzed by unsupervised hierarchical clustering and Gene Set Enrichment Analysis (GSEA) using the GenePattern software platform. RESULTS Unsupervised hierarchical clustering analysis of whole-genome gene expression profiles identified two subtypes of patients with distinct gene expression signatures. Among the most differentially expressed genes were several notable androgen-regulated genes, including TMPRSS2, NKX3-1, AZGP1, KLK3 (encoding the PSA protein) and multiple other members of the kallikrein family of serine proteases (all P <0.001, FDR <0.02). By GSEA, multiple gene sets composed of androgen-regulated genes and androgen receptor target genes were found to be significantly enriched in one of the two subtypes. Interestingly, patients from this Androgen-Up subtype were also noted to have a higher frequency of methylation of the 5AR-2 gene promoter (though not statistically significant). CONCLUSIONS Patients with BPH exhibit variable prostatic gene expression patterns. Our findings suggest the presence of distinct molecular subtypes of BPH, driven by differences in androgen gene regulation. These differences may partially explain the variable response of patients to 5-AR inhibitors and thereby inform clinical strategies for devising personalized therapy for BPH patients. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e361 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Keyan Salari More articles by this author Seth Bechis More articles by this author Rongbin Ge More articles by this author Jian Hong More articles by this author Aleksander Otsetov More articles by this author Zongwei Wang More articles by this author Shahin Tabatabaei More articles by this author Aria Olumi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...