ERG Status Is Unrelated to PSA Recurrence in Radically Operated Prostate Cancer in the Absence of Antihormonal Therapy

Purpose: About 50% of prostate cancers have TMPRSS2–ERG fusions with concurrent ERG overexpression. The aim of this study was to determine whether clinical differences exist between ERG-positive and ERG-negative cancers in surgically treated patients not exposed to antihormonal therapy. A secondary aim was to search for differences between these tumor classes. Experimental Design: A tissue microarray containing samples from more than 2,800 prostate cancers with clinical data was analyzed for ERG alterations by immunohistochemistry and FISH. Results were compared with tumor phenotype, biochemical recurrence, and molecular features considered important for prostate cancer. The effect of ERG on androgen receptor (AR)-dependent transcription was analyzed in cell lines. Results: ERG expression was found in 52.4% of 2,805 cancers with a 95% concordance between ERG expression and ERG gene rearrangement detected by FISH. ERG expression was unrelated to clinical outcome and tumor phenotype. Differences in AMACR, Annexin A3, Bcl2, CD10, ALCAM, chromogranin A, epidermal growth factor receptor, HER2, mTOR, p53, and synaptophysin status were significant but minimal in absolute numbers. The most striking difference was found for AR expression, which was markedly higher in ERG-positive cancers. In vitro studies showed ERG-dependent impairment of AR-mediated transcriptional activity. Conclusions: The striking similarities between these two types of prostate cancers rules out a major impact of ERG on tumor aggressiveness in early, not hormonally treated cancer. The marked difference in AR levels between ERG-positive and -negative cancers supports a systematic difference in potential response to hormonal therapy as previously observed in clinical trials. Clin Cancer Res; 17(18); 5878–88. ©2011 AACR.

[1]  G. Sauter,et al.  Low activated leukocyte cell adhesion molecule expression is associated with advanced tumor stage and early prostate-specific antigen relapse in prostate cancer. , 2011, Human pathology.

[2]  M. Rubin,et al.  TMPRSS2–ERG gene fusion prevalence and class are significantly different in prostate cancer of caucasian, african‐american and japanese patients , 2011, The Prostate.

[3]  A. Haese*,et al.  High level PSMA expression is associated with early psa recurrence in surgically treated prostate cancer , 2011, The Prostate.

[4]  M. Rubin,et al.  Single focus prostate cancer: pathological features and ERG fusion status. , 2011, The Journal of urology.

[5]  M. Rubin,et al.  ERG cooperates with androgen receptor in regulating trefoil factor 3 in prostate cancer disease progression. , 2010, Neoplasia.

[6]  Asha A. Nair,et al.  The ability of biomarkers to predict systemic progression in men with high-risk prostate cancer treated surgically is dependent on ERG status. , 2010, Cancer research.

[7]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[8]  S. Varambally,et al.  Antibody-based detection of ERG rearrangement-positive prostate cancer. , 2010, Neoplasia.

[9]  S-H Tan,et al.  ERG oncoprotein expression in prostate cancer: clonal progression of ERG-positive tumor cells and potential for ERG-based stratification , 2010, Prostate Cancer and Prostatic Diseases.

[10]  Zhaohui S. Qin,et al.  An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. , 2010, Cancer cell.

[11]  Hartwig Huland,et al.  Low Level Her2 Overexpression Is Associated with Rapid Tumor Cell Proliferation and Poor Prognosis in Prostate Cancer , 2010, Clinical Cancer Research.

[12]  G. Sauter,et al.  Chromosome 8p Deletions and 8q Gains are Associated with Tumor Progression and Poor Prognosis in Prostate Cancer , 2009, Clinical Cancer Research.

[13]  I. Sesterhenn,et al.  Clinicopathological behavior of single focus prostate adenocarcinoma. , 2009, The Journal of urology.

[14]  M. Rubin,et al.  ETS gene fusions in prostate cancer: from discovery to daily clinical practice. , 2009, European urology.

[15]  R. Shah,et al.  Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression , 2009, Modern Pathology.

[16]  M. Gerstein,et al.  N-myc downstream regulated gene 1 (NDRG1) is fused to ERG in prostate cancer. , 2009, Neoplasia.

[17]  Arul M Chinnaiyan,et al.  Prevalence of TMPRSS2-ERG Fusion Prostate Cancer among Men Undergoing Prostate Biopsy in the United States , 2009, Clinical Cancer Research.

[18]  M. Rubin,et al.  INTEGRATION OF ERG GENE MAPPING AND GENE‐EXPRESSION PROFILING IDENTIFIES DISTINCT CATEGORIES OF HUMAN PROSTATE CANCER , 2009, BJU international.

[19]  C. Sander,et al.  Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis , 2009, Nature Genetics.

[20]  Pier Paolo Pandolfi,et al.  Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate , 2009, Nature Genetics.

[21]  D. Dearnaley,et al.  Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. , 2009, Cancer research.

[22]  John M S Bartlett,et al.  Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  W. Gerald,et al.  TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy. , 2009, Cancer research.

[24]  Martin Schostak,et al.  Expression and prognostic relevance of annexin A3 in prostate cancer. , 2008, European urology.

[25]  O. Ludkovski,et al.  Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome , 2008, Modern Pathology.

[26]  G. Sauter,et al.  Distinct Subcellular Expression Patterns of Neutral Endopeptidase (CD10) in Prostate Cancer Predict Diverging Clinical Courses in Surgically Treated Patients , 2008, Clinical Cancer Research.

[27]  A. Haese*,et al.  Clinical significance of p53 alterations in surgically treated prostate cancers , 2008, Modern Pathology.

[28]  S. Dhanasekaran,et al.  A fluorescence in situ hybridization screen for E26 transformation-specific aberrations: identification of DDX5-ETV4 fusion protein in prostate cancer. , 2008, Cancer research.

[29]  M. Gleave,et al.  Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer , 2008, BMC Cancer.

[30]  T. Golub,et al.  Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. , 2008, Journal of the National Cancer Institute.

[31]  T. Tammela,et al.  TMPRSS2:ERG Fusion Identifies a Subgroup of Prostate Cancers with a Favorable Prognosis , 2008, Clinical Cancer Research.

[32]  J Cuzick,et al.  Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer , 2008, Oncogene.

[33]  A. Chinnaiyan,et al.  Recurrent gene fusions in prostate cancer , 2008, Nature Reviews Cancer.

[34]  J. Trachtenberg,et al.  Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer , 2007, British Journal of Cancer.

[35]  Yao-Tseng Chen,et al.  Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues , 2007, Modern Pathology.

[36]  Y Pawitan,et al.  TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort , 2007, Oncogene.

[37]  J. Damber,et al.  Molecular genetic analyses of the TMPRSS2-ERG and TMPRSS2-ETV1 gene fusions in 50 cases of prostate cancer. , 2007, Oncology reports.

[38]  J. Tchinda,et al.  Molecular characterization of TMPRSS2-ERG gene fusion in the NCI-H660 prostate cancer cell line: a new perspective for an old model. , 2007, Neoplasia.

[39]  L. Klotz,et al.  Expression of TMPRSS2:ERG gene fusion in prostate cancer cells is an important prognostic factor for cancer progression , 2007, Cancer biology & therapy.

[40]  V. Srikantan,et al.  Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome , 2006, Oncogene.

[41]  O. Kallioniemi,et al.  TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. , 2006, Cancer research.

[42]  Michael Ittmann,et al.  Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer. , 2006, Cancer research.

[43]  J. Tchinda,et al.  TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. , 2006, Cancer research.

[44]  J. Gromada,et al.  Sterol regulatory element-binding protein 1 mediates liver X receptor-beta-induced increases in insulin secretion and insulin messenger ribonucleic acid levels. , 2006, Endocrinology.

[45]  J. Tchinda,et al.  Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. , 2006, Science.

[46]  J. Cheville,et al.  Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression. , 2003, Cancer research.

[47]  Biaoyang Lin,et al.  The program of androgen-responsive genes in neoplastic prostate epithelium , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[48]  M. Graefen,et al.  Tumour grade, proliferation, apoptosis, microvessel density, p53, and bcl-2 in prostate cancers: differences between tumours located in the transition zone and in the peripheral zone. , 2002, European urology.

[49]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[50]  W. Folk,et al.  Expression of urokinase plasminogen activator and receptor in conjunction with the ets family and AP-1 complex transcription factors in high grade prostate cancers. , 2001, European journal of cancer.

[51]  L. Hood,et al.  Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. , 1999, Cancer research.

[52]  T C Gasser,et al.  Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays. , 1999, Cancer research.