Genome-wide DNA methylation events in TMPRSS2-ERG fusion-negative prostate cancers implicate an EZH2-dependent mechanism with miR-26a hypermethylation

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 coho...

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Bibliographic Details
Published in:Cancer discovery 2012-11, Vol.2 (11), p.1024-1035
Main Authors: Börno, Stefan T, Fischer, Axel, Kerick, Martin, Fälth, Maria, Laible, Mark, Brase, Jan C, Kuner, Ruprecht, Dahl, Andreas, Grimm, Christina, Sayanjali, Behnam, Isau, Melanie, Röhr, Christina, Wunderlich, Andrea, Timmermann, Bernd, Claus, Rainer, Plass, Christoph, Graefen, Markus, Simon, Ronald, Demichelis, Francesca, Rubin, Mark A, Sauter, Guido, Schlomm, Thorsten, Sültmann, Holger, Lehrach, Hans, Schweiger, Michal R
Format: Article
Language:English
Subjects:
DNA Methylation
Enhancer of Zeste Homolog 2 Protein
Epigenomics
Gene Fusion
Genome, Human
Humans
Male
MicroRNAs - genetics
Oncogene Proteins, Fusion - genetics
Polycomb Repressive Complex 2 - genetics
Prostatic Neoplasms - genetics
Prostatic Neoplasms - pathology
Transfection
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Summary: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. 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.
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.CD-12-0041