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Cosima Göbel,1,* Cansu Özden,1,* Cornelia Schroeder,2 Claudia Hube-Magg,1 Martina Kluth,1 Christina Möller-Koop,1 Emily Neubauer,1 Andrea Hinsch,1 Frank Jacobsen,1 Ronald Simon,1 Guido Sauter,1 Uwe Michl,3 Dirk Pehrke,3,4 Hartwig Huland,3 Markus Graefen,3 Thorsten Schlomm,3,4 Andreas M Luebke1 1Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 3Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4Department of Urology, Charité - Universitätsmedizin Berlin, Berlin, Germany *These authors contributed equally to this work Background: Centromere protein F (CENPF) is a key component of the kinetochore complex and plays a crucial role in chromosome segregation and cell cycle progression. Recent work suggests that CENPF upregulation is linked to aggressive tumor features in a variety of malignancies including prostate cancer. Materials and methods: Using a highly annotated tissue microarray, we analyzed CENPF protein expression from a cohort of 8,298 prostatectomized patients by immunohistochemistry to study its effect on prostate-specific antigen recurrence-free survival. Results: CENPF overexpression was found in 53% of cancers, and was linked to higher Gleason grade, advanced pathological tumor stage, accelerated cell proliferation, and lymph node metastasis (p

Martina Kluth,1,* Heinke Volta,1,* Mohammad Hussein,1 Billurvan Taskin,1 Sohall Frogh,1 Christina Möller-Koop,1 Franziska Büscheck,1 Frank Jacobsen,1 Maria Christina Tsourlakis,1 Andreas M Lübke,1 Andrea Hinsch,1 Till Clauditz,1 Markus Graefen,2 Hans Heinzer,2 Hartwig Huland,2 Sarah Minner,1 Guido Sauter,1 Waldemar Wilczak,1 Thorsten Schlomm,2–4 Ronald Simon1 1Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 3Department of Urology, Section for Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4Department of Urology, Charitè Universitätsmedizin Berlin, Berlin, Germany *These authors contributed equally to this work Introduction: Deletion of 3p13 is one of the most common alterations in prostate cancer preferentially occurring in tumors with TMPRSS2:ERG fusion. The cause for the striking association between 3p13 loss and ERG fusion is unknown. Methods: Here, we made use of a preexisting heterogeneity prostate cancer tissue microarray including ten tissue spots from ten different tumor areas of 317 cancers to examine the spatial distribution of 3p13 deletions (determined by fluorescence in situ hybridization) in prostate cancer areas with and without ERG overexpression (determined by immunohistochemistry). Results: 3p13 deletions were found in 61 of 299 (20.4%) and ERG positivity in 174 of 317 (54.9%) interpretable cancers. The likelihood of 3p13 loss was twice as high in ERG-positive cancers (39/152, 25.7%) than in ERG-negative cancers (17/124, 13.7%, P=0.010). At least three tissue spots were interpretable for 3p13 deletion status in 279 cancers: only these were used for heterogeneity assessment. Among these tumors, 58 (20.8%) had a 3p13 deletion and 221 (79.2%) were undeleted. The majority of 3p13-deleted cancers showed marked intratumoral heterogeneity. Areas with and without 3p13 loss were found in 50 (18%) of 279 cancers with three or more interpretable tissue spots, while only eight (3%) tumors had a homogeneous 3p13 loss. Comparison with ERG data revealed that ERG fusion usually precede 3p13 deletions. In total, 26 (66.7%) of 39 cancers with ERG and 3p13 alteration had only focal 3p13 deletions in an otherwise ERG-positive background. In contrast, none of the cancers showed a pattern that would be consistent with 3p13 deletion preceding ERG fusion. Conclusion: Our study identifies 3p13 deletion as a highly heterogeneous alteration in prostate cancer preferentially developing at rather late stages of progression in TMPRSS2:ERG fusion-positive tumors. Keywords: 3p13 deletion, prostate cancer, heterogeneity, TMPRSS2:ERG fusion, tissue microarray