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

• Published in: Oncotarget Vol. 7; no. 17; pp. 24326 - 24338
• Main Authors: Spans, Lien, Van den Broeck, Thomas, Smeets, Elien, Prekovic, Stefan, Thienpont, Bernard, Lambrechts, Diether, Karnes, R Jeffrey, Erho, Nicholas, Alshalalfa, Mohammed, Davicioni, Elai, Helsen, Christine, Gevaert, Thomas, Tosco, Lorenzo, Haustermans, Karin, Lerut, Evelyne, Joniau, Steven, Claessens, Frank
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 26.04.2016
• Subjects: Aged; DNA Methylation; Epigenomics; Exome - genetics; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Genomics; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Research Paper; Risk Factors; Sequence Analysis, DNA - methods; DNA hydroxymethylation; TET1; genomics; high-risk prostate cancer; epigenetics
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8220

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.