PD52-07 TANDEM HISTONE METHYLTRANSFERASE UPREGULATION DEFINES A UNIQUE AGGRESSIVE PROSTATE CANCER PHENOTYPE

Abstract

You have accessJournal of UrologyProstate Cancer: Markers II (PD52)1 Apr 2020PD52-07 TANDEM HISTONE METHYLTRANSFERASE UPREGULATION DEFINES A UNIQUE AGGRESSIVE PROSTATE CANCER PHENOTYPE Mikolaj Filon*, Joseph Gawdzik, Andrew Truong, Bing Yang, Rehaan Machhi, and David F Jarrard Mikolaj Filon*Mikolaj Filon* More articles by this author , Joseph GawdzikJoseph Gawdzik More articles by this author , Andrew TruongAndrew Truong More articles by this author , Bing YangBing Yang More articles by this author , Rehaan MachhiRehaan Machhi More articles by this author , and David F JarrardDavid F Jarrard More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000954.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PC) is characterized by dysregulated epigenetic signaling including altered levels of histone methylation and expression of histone methyltransferases (HMTs). Enhancer of Zeste Homolog 2 (EZH2) and nuclear receptor binding SET domain 2 (NSD2) are HMTs that tri-methylate H3K27 and di-methylate H3K36 respectively to regulate the transcriptional potential of genomic loci. These enzymes are upregulated in PC and represent putative drug targets. Here we investigate if these HMTs coregulate in tumors, and whether EZH2/NSD2 co-expression associates with cancer outcomes. METHODS: PC tissue microarrays (TMAs) constructed from benign, localized and metastatic PC tissue from 183 patients were analyzed, along with 142 cores from a castration resistant PC array. NSD2 and EZH2 protein levels were quantified with immunohistochemical staining using image analysis. Primary PC samples from The Cancer Genome Atlas (TCGA; n=498) and Memorial Sloan Kettering Cancer Center (MSKCC; n=150) were queried using cBioportal for cancer genomics. RNA-seq data was used to identify patients in the top quartile of NSD2 and EZH2 co-expression, who were compared to the remainder for Gleason Grade, tumor stage, and disease-free status. RESULTS: Analysis of TMA data shows the percentage of epithelial nuclei with NSD2/EZH2 co-expression was increased in CRPC compared to hormone sensitive PC (HSPC) tissues (p=0.02). Analysis of HSPC reveals an enrichment of co-expression in metastatic PC tissue relative to benign tissue (p<0.05). Histologic disease progression in primary tissue was associated with an increase in the proportion of patients from the top quartile of EZH2/NSD2 co-localization (p=0.01). Analysis of clinical data in the TCGA and MSKCC databases reveals a significantly higher proportion of patients in the top 25% of EZH2/NSD2 co-expression with Gleason scores 8-10 (p<0.001), with stage T4 and T3a/b tumors (p<0.01). This patient subset shows reduced disease-free survival at 60 months (p<0.01) (Figure 1). CONCLUSIONS: Patients with robust EZH2/NSD2 co-expression are over-represented in CRPC TMAs, in patients with metastases, and in those with shorter disease-free survival. These results suggest that co-expression of these HMTs identify a more aggressive PC subtype and licenses them as a therapeutic target. Source of Funding: U.S Department of Defence PC180847 (J.G) © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1092-e1092 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mikolaj Filon* More articles by this author Joseph Gawdzik More articles by this author Andrew Truong More articles by this author Bing Yang More articles by this author Rehaan Machhi More articles by this author David F Jarrard More articles by this author Expand All Advertisement PDF downloadLoading ...