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      Preliminary Results of Noninvasive Detection of TMPRSS2:ERG Gene Fusion in a Cohort of Patients With Localized Prostate Cancer

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          Abstract

          Purpose

          The aim of this study was to evaluate TMPRSS2:ERG fusion rates in tissue, urine, blood, and pubic hair samples in a cohort of patients with localized prostate cancer and to correlate these findings with various clinicopathological parameters.

          Materials and Methods

          A cohort of 40 patients undergoing radical prostatectomy for localized prostate cancer (RRP group) and 10 control patients undergoing prostate biopsy were enrolled between 2006 and 2008. Urine, pubic hair, and peripheral blood samples were obtained following prostatic massage before the needle biopsy or radical prostatectomy. Quantitative polymerase chain reaction analysis was performed on all collected samples.

          Results

          The patients' mean age was 62.4 (±5.5) years. We observed higher expressions of TMPRSS2:ERG fusion in tissue, urine, and blood samples from the RRP group than in samples from the control group. Overall, the fusion was present in urine samples of 23 RRP patients (57.5%). To predict high-stage cancer (>T3a), the Gleason score was the only significant factor in the logistic regression analysis (score, 10.579; p=0.001). Quantitative evaluation of the gene fusion in tissue (Pearson r=0.36, p=0.011) and urine (Pearson r=0.34, p=0.014) samples had a significant positive correlation with the preoperative prostate-specific antigen level.

          Conclusions

          Urine sediments collected after prostatic massage appear to be a feasible noninvasive method of detecting TMPRSS2:ERG fusion. The Gleason score is the only significant factor to predict high-stage cancer (>T3a). No correlation between TMPRSS2:ERG gene fusion status and tumor stage, Gleason grade, prostate-specific antigen level, or surgical margin status was observed.

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          Most cited references26

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          Recurrent gene fusions in prostate cancer.

          The discovery of recurrent gene fusions in a majority of prostate cancers has important clinical and biological implications in the study of common epithelial tumours. Gene fusion and chromosomal rearrangements were previously thought to be primarily the oncogenic mechanism of haematological malignancies and sarcomas. The prostate cancer gene fusions that have been identified thus far are characterized by 5' genomic regulatory elements, most commonly controlled by androgen, fused to members of the Ets family of transcription factors, leading to the overexpression of oncogenic transcription factors. Ets gene fusions probably define a distinct class of prostate cancer, and this might have a bearing on diagnosis, prognosis and rational therapeutic targeting.
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            TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort.

            The identification of the TMPRSS2:ERG fusion in prostate cancer suggests that distinct molecular subtypes may define risk for disease progression. In surgical series, TMPRSS2:ERG fusion was identified in 50% of the tumors. Here, we report on a population-based cohort of men with localized prostate cancers followed by expectant (watchful waiting) therapy with 15% (17/111) TMPRSS2:ERG fusion. We identified a statistically significant association between TMPRSS2:ERG fusion and prostate cancer specific death (cumulative incidence ratio=2.7, P<0.01, 95% confidence interval=1.3-5.8). Quantitative reverse-transcription-polymerase chain reaction demonstrated high ets-related [corrected] gene (ERG) expression to be associated with TMPRSS2:ERG fusion (P<0.005). These data suggest that TMPRSS2:ERG fusion prostate cancers may have a more aggressive phenotype, possibly mediated through increased ERG expression.
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              TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer.

              Prostate cancer is a common and clinically heterogeneous disease with marked variability in progression. The recent identification of gene fusions of the 5'-untranslated region of TMPRSS2 (21q22.3) with the ETS transcription factor family members, either ERG (21q22.2), ETV1 (7p21.2), or ETV4 (17q21), suggests a mechanism for overexpression of the ETS genes in the majority of prostate cancers. In the current study using fluorescence in situ hybridization (FISH), we identified the TMPRSS2:ERG rearrangements in 49.2% of 118 primary prostate cancers and 41.2% of 18 hormone-naive lymph node metastases. The FISH assay detected intronic deletions between ERG and TMPRSS2 resulting in TMPRSS2:ERG fusion in 60.3% (35 of 58) of the primary TMPRSS2:ERG prostate cancers and 42.9% (3 of 7) of the TMPRSS2:ERG hormone-naive lymph node metastases. A significant association was observed between TMPRSS2:ERG rearranged tumors through deletions and higher tumor stage and the presence of metastatic disease involving pelvic lymph nodes. Using 100K oligonucleotide single nucleotide polymorphism arrays, a homogeneous deletion site between ERG and TMPRSS2 on chromosome 21q22.2-3 was identified with two distinct subclasses distinguished by the start point of the deletion at either 38.765 or 38.911 Mb. This study confirms that TMPRSS2:ERG is fused in approximately half of the prostate cancers through deletion of genomic DNA between ERG and TMPRSS2. The deletion as cause of TMPRSS2:ERG fusion is associated with clinical features for prostate cancer progression compared with tumors that lack the TMPRSS2:ERG rearrangement.
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                Author and article information

                Journal
                Korean J Urol
                Korean J Urol
                KJU
                Korean Journal of Urology
                The Korean Urological Association
                2005-6737
                2005-6745
                June 2013
                12 June 2013
                : 54
                : 6
                : 359-363
                Affiliations
                Department of Urology, Marmara University School of Medicine, Istanbul, Turkey.
                Author notes
                Corresponding Author: Naside Mangir. Department of Urology, Marmara University School of Medicine, FevziÇakmak Mahallesi, Mimar Sinan Caddesi No:41, Pendik/Istanbul 34899, Turkey. TEL: +90-216-6254768, FAX: +90-216-6570695, nasidemangir@ 123456yahoo.com
                Article
                10.4111/kju.2013.54.6.359
                3685633
                23789042
                f5ac88c1-5dec-46e4-b589-05675e679d32
                © The Korean Urological Association, 2013

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 18 December 2012
                : 20 February 2013
                Categories
                Original Article
                Urological Oncology

                Urology
                prognosis,prostate neoplasms,tmprss2-erg fusion protein
                Urology
                prognosis, prostate neoplasms, tmprss2-erg fusion protein

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