Nuclear up regulation of the BRCA1-associated ubiquitinase BAP1 is associated with tumor aggressiveness in prostate cancers lacking the TMPRSS2:ERG fusion.

Stefan Steurer,Till S Clauditz,Maria Christina Tsourlakis,Sarah Minner,Doris Höflmayer,Hans Heinzer,Franziska Büscheck,Cornelia Schroeder,Christoph Fraune,Sören Weidemann,Ronald Simon,Markus Graefen,Jan Meiners,Thorsten Schlomm,Patrick Lebok,Andreas M Luebke,Hartwig Huland,Guido Sauter,Cosima Göbel,David Dum,Lara Schwemmer,Alexander Haese,Jakob R Izbicki ,Claudia Hube‐Magg

doi:10.18632/oncotarget.27270

Abstract

Loss of the putative tumor suppressor BAP1 is a candidate biomarker for adverse prognosis in many cancer types, but conversely for improved survival in others. Studies on the expression and prognostic role of BAP1 in prostate cancer are currently lacking. We used a tissue microarray of 17,747 individual prostate cancer samples linked with comprehensive pathological, clinical and molecular data and studied the immunohistochemical expression of BAP1. BAP1 expression was typically up regulated in cancers as compared to adjacent normal prostatic glands. In 15,857 cancers, BAP1 staining was weak in 3.3%, moderate in 41.6% and strong in 17.4%. Strong BAP1 staining was associated with advanced tumor stage (p<0.0001), high classical and quantitative Gleason grade (p<0.0001), lymph node metastasis (p<0.0001), a positive surgical margin (p=0.0019) and early biochemical recurrence (p<0.0001). BAP1 expression was linked to ERG-fusion type cancers, with strong BAP1 staining in 12% of ERG-negative, but 30% of ERG-positive cancers (p<0.0001). Subset analyses in 5,415 cancers with and 4,217 cancers without TMPRSS2:ERG fusion revealed that these associations with tumor phenotype and patient outcome were largely driven by the subset of ERG-negative tumors. Multivariate analysis revealed that the prognostic impact was independent of established prognostic features in ERG negative p<0.001) but not in ERG positive cancers. BAP1 expression was further linked to androgen receptor (AR) expression: Only 2% of AR-negative, but 33% of strongly AR expressing cancers had strong BAP1 expression (p<0.0001). In conclusion, this study shows that BAP1 up regulation is linked to prostate cancer progression and aggressiveness.

Highlights

Prostate cancer (PCa) is the most diagnosed cancer among males in Western societies [1]
BRCA-1-associated Protein 1 (BAP1) expression was further linked to androgen receptor (AR) expression: Only 2% of AR-negative, but 33% of strongly AR expressing cancers had strong BAP1 expression (p
In this study we show that nuclear BAP1 expression is an independent predictor of poor prognosis in ERG negative PCa

Summary

Introduction

Prostate cancer (PCa) is the most diagnosed cancer among males in Western societies [1] At this point, established prognosticators include histological analysis of biopsies to determine Gleason score and tumor extent, prostate-specific antigen (PSA) and clinical stage. Current diagnostic analysis still proves prone to inaccuracies that could be reduced by finding a reliable and clinically applicable molecular marker. This could spare patients with otherwise harmless tumors the negative effects of treatment (e.g. incontinence and erectile dysfunction), and identify those patients with aggressive disease for whom the benefits of treatment outweigh its harm [2]. Genomic deletion of its locus at 3p21 or loss of BAP1

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Results

Conclusion