Genomic and epigenomic analysis of high-risk prostate cancer reveals changes in hydroxymethylation and TET1
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Lien Spans1,2, Thomas Van den Broeck1,3, Elien Smeets1, Stefan Prekovic1, Bernard Thienpont4,5, Diether Lambrechts4,5, R. Jeffrey Karnes6, Nicholas Erho7, Mohammed Alshalalfa7, Elai Davicioni7, Christine Helsen1, Thomas Gevaert8, Lorenzo Tosco3, Karin Haustermans9, Evelyne Lerut10,11, Steven Joniau3, Frank Claessens1
1Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, Leuven, Belgium
2Current address: Laboratory for Genetics of Malignant Disorders, Department of Human Genetics, University of Leuven, Campus Gasthuisberg, Leuven, Belgium
3Department of Urology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium
4Vesalius Research Center, VIB, Leuven, Belgium
5Laboratory of Translational Genetics, Department of Oncology, University of Leuven, Campus Gasthuisberg, Leuven, Belgium
6Department of Urology, Mayo Clinic, Rochester, MN, USA
7Research and Development, GenomeDx Biosciences, Inc., Vancouver, BC, Canada
8Organ Systems, Department of Development and Regeneration, University of Leuven, Campus Gasthuisberg, Leuven, Belgium
9Laboratory of Experimental Radiotherapy, Department of Oncology, University of Leuven, Campus Gasthuisberg, Leuven, Belgium
10Translational Cell & Tissue Research, Department of Imaging and Pathology, University Hospitals Leuven, Leuven, Belgium
Frank Claessens, e-mail: Frank.Claessens@kuleuven.be
Keywords: high-risk prostate cancer, genomics, TET1, epigenetics, DNA hydroxymethylation
Received: August 07, 2015 Accepted: March 04, 2016 Published: March 21, 2016
The clinical heterogeneity of prostate cancer (PCa) makes it difficult to identify those patients that could benefit from more aggressive treatments. As a contribution to a better understanding of the genomic changes in the primary tumor that are associated with the development of high-risk disease, we performed exome sequencing and copy number determination of a clinically homogeneous cohort of 47 high-risk PCas. We confirmed recurrent mutations in SPOP, PTEN and TP53 among the 850 point mutations we detected. In seven cases, we discovered genomic aberrations in the TET1 (Ten-Eleven Translocation 1) gene which encodes a DNA hydroxymethylase than can modify methylated cytosines in genomic DNA and thus is linked with gene expression changes. TET1 protein levels were reduced in tumor versus non-tumor prostate tissue in 39 of 40 cases. The clinical relevance of changes in TET1 levels was demonstrated in an independent PCa cohort, in which low TET1 mRNA levels were significantly associated with worse metastases-free survival. We also demonstrate a strong reduction in hydroxymethylated DNA in tumor tissue in 27 of 41 cases. Furthermore, we report the first exploratory (h)MeDIP-Seq analyses of eight high-risk PCa samples. This reveals a large heterogeneity in hydroxymethylation changes in tumor versus non-tumor genomes which can be linked with cell polarity.
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