Research Papers:

Genomic and epigenomic analysis of high-risk prostate cancer reveals changes in hydroxymethylation and TET1

Lien Spans, Thomas Van den Broeck, Elien Smeets, Stefan Prekovic, Bernard Thienpont, Diether Lambrechts, R. Jeffrey Karnes, Nicholas Erho, Mohammed Alshalalfa, Elai Davicioni, Christine Helsen, Thomas Gevaert, Lorenzo Tosco, Karin Haustermans, Evelyne Lerut, Steven Joniau and Frank Claessens _

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Oncotarget. 2016; 7:24326-24338. https://doi.org/10.18632/oncotarget.8220

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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

11PEARL Consortium

Correspondence to:

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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PII: 8220