title: Epigenomic profiling of prostate cancer identifies differentially methylated genes in TMPRSS2:ERG fusion-positive versus fusion-negative tumors.
abstract: BACKGROUND
  About half of all prostate cancers harbor the TMPRSS2:ERG (T2E) gene fusion. While T2E-positive and T2E-negative tumors represent specific molecular subtypes of prostate cancer (PCa), previous studies have not yet comprehensively investigated how these tumor subtypes differ at the epigenetic level. We therefore investigated epigenome-wide DNA methylation profiles of PCa stratified by T2E status.
  
  
  RESULTS
  The study included 496 patients with clinically localized PCa who had a radical prostatectomy as primary treatment for PCa. Fluorescence in situ hybridization (FISH) "break-apart" assays were used to determine tumor T2E-fusion status, which showed that 266 patients (53.6 %) had T2E-positive PCa. The study showed global DNA methylation differences between tumor subtypes. A large number of differentially methylated CpG sites were identified (false-discovery rate [FDR] Q-value <0.00001; n = 27,876) and DNA methylation profiles accurately distinguished between tumor T2E subgroups. A number of top-ranked differentially methylated CpGs in genes (FDR Q-values ≤1.53E-29) were identified: C3orf14, CACNA1D, GREM1, KLK10, NT5C, PDE4D, RAB40C, SEPT9, and TRIB2, several of which had a corresponding alteration in mRNA expression. These genes may have various roles in the pathogenesis of PCa, and the calcium-channel gene CACNA1D is a known ERG-target. Analysis of The Cancer Genome Atlas (TCGA) data provided confirmatory evidence for our findings.
  
  
  CONCLUSIONS
  This study identified substantial differences in DNA methylation profiles of T2E-positive and T2E-negative tumors, thereby providing further evidence that different underlying oncogenic pathways characterize these molecular subtypes.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA USA ; Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Milan S
authors.initials: MS
authors.lastname: Geybels
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR USA.
authors.forename: Joshi J
authors.initials: JJ
authors.lastname: Alumkal
authors.affiliation: Institute of Human Genetics and Department of Urology, Faculty of Medicine, University of Ulm, Ulm, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Luedeke
authors.affiliation: Institute of Human Genetics and Department of Urology, Faculty of Medicine, University of Ulm, Ulm, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Rinckleb
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA USA ; Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NC Research Triangle Park, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA USA.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Shui
authors.affiliation: Illumina, Inc., San Diego, CA USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Bibikova
authors.affiliation: Illumina, Inc., San Diego, CA USA.
authors.forename: Brandy
authors.initials: B
authors.lastname: Klotzle
authors.affiliation: Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Piet A
authors.initials: PA
authors.lastname: van den Brandt
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD USA.
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
authors.affiliation: Illumina, Inc., San Diego, CA USA ; Present Address: AnchorDx Corp., Guangzhou, 510300 People's Republic of China.
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.affiliation: MD Anderson Cancer Center, Houston, TX USA.
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Institute of Human Genetics and Department of Urology, Faculty of Medicine, University of Ulm, Ulm, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Maier
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA USA ; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stanford
keywords: C3orf14; CACNA1D; CpG site; DNA methylation; ERG; Epigenetics; Epigenomic profiling; GREM1; Gene fusion; KLK10; NT5C; PDE4D; Prostate cancer; RAB40C; SEPT9; TCGA; TMPRSS2; TRIB2; Tumor tissue; Unsupervised clustering; mRNA expression