title: Genome-wide DNA methylation events in TMPRSS2-ERG fusion-negative prostate cancers implicate an EZH2-dependent mechanism with miR-26a hypermethylation.
abstract: Prostate cancer is the second most common cancer among men worldwide. Alterations in the DNA methylation pattern can be one of the leading causes for prostate cancer formation. This study is the first high-throughput sequencing study investigating genome-wide DNA methylation patterns in a large cohort of 51 tumor and 53 benign prostate samples using methylated DNA immunoprecipitation sequencing. Comparative analyses identified more than 147,000 cancer-associated epigenetic alterations. In addition, global methylation patterns show significant differences based on the TMPRSS2-ERG rearrangement status. We propose the hypermethylation of miR-26a as an alternative pathway of ERG rearrangement-independent EZH2 activation. The observed increase in differential methylation events in fusion-negative tumors can explain the tumorigenic process in the absence of genomic rearrangements.
  
  
  CONCLUSIONS
  In contrast to TMPRSS2-ERG -rearranged tumors, the pathomechanism for gene fusion-negative tumors is completely unclear. Using a sequencing-based approach, our work uncovers significant global epigenetic alterations in TMPRSS2-ERG gene fusion-negative tumors and provides a mechanistic explanation for the tumor formation process.
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Stefan T
authors.initials: ST
authors.lastname: Börno
authors.forename: Axel
authors.initials: A
authors.lastname: Fischer
authors.forename: Martin
authors.initials: M
authors.lastname: Kerick
authors.forename: Maria
authors.initials: M
authors.lastname: Fälth
authors.forename: Mark
authors.initials: M
authors.lastname: Laible
authors.forename: Jan C
authors.initials: JC
authors.lastname: Brase
authors.forename: Ruprecht
authors.initials: R
authors.lastname: Kuner
authors.forename: Andreas
authors.initials: A
authors.lastname: Dahl
authors.forename: Christina
authors.initials: C
authors.lastname: Grimm
authors.forename: Behnam
authors.initials: B
authors.lastname: Sayanjali
authors.forename: Melanie
authors.initials: M
authors.lastname: Isau
authors.forename: Christina
authors.initials: C
authors.lastname: Röhr
authors.forename: Andrea
authors.initials: A
authors.lastname: Wunderlich
authors.forename: Bernd
authors.initials: B
authors.lastname: Timmermann
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Markus
authors.initials: M
authors.lastname: Graefen
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schlomm
authors.forename: Holger
authors.initials: H
authors.lastname: Sültmann
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.forename: Michal R
authors.initials: MR
authors.lastname: Schweiger
mesh_terms: D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D057890:Epigenomics; D050939:Gene Fusion; D015894:Genome, Human; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D014162:Transfection
chemical_list: D000071221:Enhancer of Zeste Homolog 2 Protein; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D063151:Polycomb Repressive Complex 2; C528163:MIRN26 microRNA, human; C515553:TMPRSS2-ERG fusion protein, human; C498409:EZH2 protein, human