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

Doris Höflmayer,Martina Kluth,Karsten Rippe,Markus Graefen,Thorsten Schlomm,Guido Sauter,Claudia Hube‐Magg,Eike Burandt,Sarah Minner,Stefan Steurer,Hans Heinzer,Hartwig Huland,Andrea Hinsch,Waldemar Wilczak,Maria Christina Tsourlakis,Alexander Haese,Frank Jacobsen,Franziska Büscheck,Rainer König,Ronald Simon,Marcus Oswald,Cornelia Schroeder,Amélie Steinhoff,Alexandra M Poos

doi:10.1002/1878-0261.12597

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.

Highlights

Prostate cancer has an incidence of 76 in 100 000 men and a mortality rate of 10 in 100 000 men in Western Europe (Bray et al, 2018)
The binding of CCCTC-binding factor (CTCF) to the first exon of the hTERT gene was reported to suppress its expression in telomerase-negative cells but not in cancer cells in a DNA methylation-dependent manner (Renaud et al, 2007)
The tissue microarray (TMA) was annotated with results on ERG expression (Minner et al, 2011), ERG break-apart fluorescence in situ hybridization (FISH) (Tsourlakis et al, 2016), Ki67 labeling index (Ki67-LI) (Tennstedt et al, 2012), and deletion status of 5q21 (CHD1 (Burkhardt et al, 2013), 6q15 (MAP3K7) (Kluth et al, 2013), 10q23 [phosphatase and tensin homolog (PTEN)] (Krohn et al, 2012), and 3p13 (FOXP1 (Krohn et al, 2013)

Summary

Introduction

Prostate cancer has an incidence of 76 in 100 000 men and a mortality rate of 10 in 100 000 men in Western Europe (Bray et al, 2018). The decision between radical prostatectomy and observation is guided by established pretreatment prognostic parameters [Gleason grade and tumor extent on biopsies, preoperative prostate-specific antigen (PSA), and clinical stage] (Thompson and Tangen, 2012; Wilt et al, 2012). The binding of CTCF to the first exon of the hTERT gene was reported to suppress its expression in telomerase-negative cells but not in cancer cells in a DNA methylation-dependent manner (Renaud et al, 2007) In line with this finding, treatment with a histone deacetylase inhibitor induced histone hyperacetylation and loss of CpG methylation, which facilitated CTCF binding at this locus (Meeran et al, 2010). The database attached to our TMA contains pathological and clinical follow-up data, as well as abundant molecular data on key molecular alterations of this disease such as ERG fusion and various genomic deletions

Methods

Results

Conclusion