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      Expression of CCCTC‐binding factor (CTCF) is linked to poor prognosis in prostate cancer

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          Abstract

          The chromatin‐organizing factor CCCTC‐binding factor (CTCF) is involved in transcriptional regulation, DNA‐loop formation, and telomere maintenance. To evaluate the clinical impact of CTCF in prostate cancer, we analyzed CTCF expression by immunohistochemistry on a tissue microarray containing 17 747 prostate cancers. Normal prostate tissue showed negative to low CTCF expression, while in prostate cancers, CTCF expression was seen in 7726 of our 12 555 (61.5%) tumors and was considered low in 44.6% and high in 17% of cancers. Particularly, high CTCF expression was significantly associated with the presence of the transmembrane protease, serine 2:ETS‐related gene fusion: Only 10% of ERG‐negative cancers, but 30% of ERG‐positive cancers had high‐level CTCF expression ( P < 0.0001). CTCF expression was significantly associated with advanced pathological tumor stage, high Gleason grade ( P < 0.0001 each), nodal metastasis ( P = 0.0122), and early biochemical recurrence ( P < 0.0001). Multivariable modeling revealed that the prognostic impact of CTCF was independent from established presurgical parameters such as clinical stage and Gleason grade of the biopsy. Comparison with key molecular alterations showed strong associations with the expression of the Ki‐67 proliferation marker and presence of phosphatase and tensin homolog deletions ( P < 0.0001 each). The results of our study identify CTCF expression as a candidate biomarker for prognosis assessment in prostate cancer.

          Abstract

          The transcriptional repressor CCCTC‐binding factor, which is involved in modeling the chromatin face in the nucleus of a cell, was analyzed for its expression in prostate cancer. We report here that its upregulation was associated with a shorter prostate‐specific antigen recurrence‐free survival after prostatectomy in a large cohort of prostate cancer patients.

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          Most cited references 32

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          Tissue microarrays for high-throughput molecular profiling of tumor specimens.

          Many genes and signalling pathways controlling cell proliferation, death and differentiation, as well as genomic integrity, are involved in cancer development. New techniques, such as serial analysis of gene expression and cDNA microarrays, have enabled measurement of the expression of thousands of genes in a single experiment, revealing many new, potentially important cancer genes. These genome screening tools can comprehensively survey one tumor at a time; however, analysis of hundreds of specimens from patients in different stages of disease is needed to establish the diagnostic, prognostic and therapeutic importance of each of the emerging cancer gene candidates. Here we have developed an array-based high-throughput technique that facilitates gene expression and copy number surveys of very large numbers of tumors. As many as 1000 cylindrical tissue biopsies from individual tumors can be distributed in a single tumor tissue microarray. Sections of the microarray provide targets for parallel in situ detection of DNA, RNA and protein targets in each specimen on the array, and consecutive sections allow the rapid analysis of hundreds of molecular markers in the same set of specimens. Our detection of six gene amplifications as well as p53 and estrogen receptor expression in breast cancer demonstrates the power of this technique for defining new subgroups of tumors.
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            CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease.

            CTCF is an evolutionarily conserved zinc finger (ZF) phosphoprotein that binds through combinatorial use of its 11 ZFs to approximately 50 bp target sites that have remarkable sequence variation. Formation of different CTCF-DNA complexes, some of which are methylation-sensitive, results in distinct functions, including gene activation, repression, silencing and chromatin insulation. Disrupting the spectrum of target specificities by ZF mutations or by abnormal selective methylation of targets is associated with cancer. CTCF emerges, therefore, as a central player in networks linking expression domains with epigenetics and cell growth regulation.
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              Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer.

              Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic "androgen-type" pathomechanism in EO-PCA. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                r.simon@uke.de
                Journal
                Mol Oncol
                Mol Oncol
                10.1002/(ISSN)1878-0261
                MOL2
                Molecular Oncology
                John Wiley and Sons Inc. (Hoboken )
                1574-7891
                1878-0261
                29 November 2019
                January 2020
                : 14
                : 1 ( doiID: 10.1002/mol2.v14.1 )
                : 129-138
                Affiliations
                [ 1 ] Institute of Pathology University Medical Center Hamburg‐Eppendorf Germany
                [ 2 ] Martini‐Clinic Prostate Cancer Center University Medical Center Hamburg‐Eppendorf Germany
                [ 3 ] Department of Urology Charité ‐ Universitätsmedizin Berlin Germany
                [ 4 ] Integrated Research and Treatment Center Center for Sepsis Control and Care (CSCC) Jena University Hospital Germany
                [ 5 ] Network Modeling Leibniz Institute for Natural Product Research and Infection Biology ‐ Hans Knöll Institute Jena Germany
                [ 6 ] Faculty of Biosciences Heidelberg University Germany
                [ 7 ] Division of Chromatin Networks German Cancer Research Center (DKFZ) and Bioquant Heidelberg Germany
                [ 8 ] General, Visceral and Thoracic Surgery Department and Clinic University Medical Center Hamburg‐Eppendorf Germany
                Author notes
                [* ] Correspondence

                R. Simon, Institute of Pathology, University Medical Center Hamburg‐Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

                Fax: +49 40 7410 55997

                Tel: +49 40 7410 57214

                E‐mail: r.simon@ 123456uke.de

                Article
                MOL212597
                10.1002/1878-0261.12597
                6944131
                31736271
                © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 5, Tables: 2, Pages: 10, Words: 5531
                Product
                Funding
                Funded by: German Federal Ministry of Education and Research (BMBF) , open-funder-registry 10.13039/501100002347;
                Award ID: 01EO1002
                Award ID: 01EO1502
                Award ID: 01ZX130
                Award ID: 01ZX1602
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                January 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.4 mode:remove_FC converted:06.01.2020

                Oncology & Radiotherapy

                ctcf, tma, prostate cancer, deletion

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