title: Genomic and epigenomic analysis of high-risk prostate cancer reveals changes in hydroxymethylation and TET1.
abstract: 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.
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.|Current address: Laboratory for Genetics of Malignant Disorders, Department of Human Genetics, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Spans
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.|Department of Urology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Van den Broeck
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Elien
authors.initials: E
authors.lastname: Smeets
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Prekovic
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Translational Genetics, Department of Oncology, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thienpont
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Translational Genetics, Department of Oncology, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, MN, USA.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Karnes
authors.affiliation: Research and Development, GenomeDx Biosciences, Inc., Vancouver, BC, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Erho
authors.affiliation: Research and Development, GenomeDx Biosciences, Inc., Vancouver, BC, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alshalalfa
authors.affiliation: Research and Development, GenomeDx Biosciences, Inc., Vancouver, BC, Canada.
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Helsen
authors.affiliation: Organ Systems, Department of Development and Regeneration, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gevaert
authors.affiliation: Department of Urology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Tosco
authors.affiliation: Laboratory of Experimental Radiotherapy, Department of Oncology, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Haustermans
authors.affiliation: Translational Cell & Tissue Research, Department of Imaging and Pathology, University Hospitals Leuven, Leuven, Belgium.|PEARL Consortium.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lerut
authors.affiliation: Department of Urology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Joniau
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Claessens
mesh_terms: D000368:Aged; D019175:DNA Methylation; D057890:Epigenomics; D059472:Exome / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D011518:Proto-Oncogene Proteins; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human
keywords: DNA hydroxymethylation; TET1; epigenetics; genomics; high-risk prostate cancer