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      Cysteine- rich secretory protein 3 (CRISP3), ERG and PTEN define a molecular subtype of prostate cancer with implication to patients’ prognosis

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          Abstract

          Cysteine- rich secretory protein 3 (CRISP3) prognostic significance in prostate cancer (PCA) has generated mixed result. Herein, we investigated and independently validated CRISP3 expression in relation to ERG and PTEN genomic aberrations and clinical outcome. CRISP3 protein expression was examined by immunohistochemistry using a cohort of patients with localized PCA (n = 215) and castration resistant PCA (CRPC) (n = 46). The Memorial Sloan Kettering (MSKCC) and Swedish cohorts were used for prognostic validation. Results showed, CRISP3 protein intensity to be significantly associated with neoplastic epithelium, being highest in CRPC vs. benign prostate tissue (p < 0.0001), but was not related to Gleason score (GS). CRISP3 mRNA was significantly associated with higher GS (p = 0.022 in MSKCC, p = 1.1e-4 in Swedish). Significant association between CRISP3 expression and clinical outcome was documented at the mRNA but not the protein expression levels. CRISP3 mRNA expression was related to biochemical recurrence in the MSKCC (p = 0.038) and lethal disease in the Swedish cohort (p = 0.0086) and retained its prognostic value in the subgroup of patients with GS 6 & 7. Furthermore, CRISP3 protein and mRNA expression was significantly associated with positive ERG status and with PTEN deletions. Functional biology analysis documented phenylalanine metabolism as the most significant pathway governing high CRISP3 and ERG expression in this subtype of PCA. In conclusion, the combined status of CRISP3, ERG and PTEN define a molecular subtype of PCA with poorest and lethal outcome. Assessing their combined value may be of added value in stratifying patients into different prognostic groups and identify those with poorest clinical outcome.

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          Most cited references24

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          The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma.

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            International trends and patterns of prostate cancer incidence and mortality.

            Prostate cancer is the most commonly diagnosed cancer in western men, and incidence is rising rapidly in most countries, including low-risk populations. Age-adjusted incidence and mortality rates from 15 and 13 countries between 1973-77 and 1988-92, respectively, were compared to provide leads for future analytic studies. Large increases in both incidence and mortality rates of prostate cancer were seen for all countries. For incidence, increases were more pronounced in the United States, Canada, Australia, France and the Asian countries, while the increases in medium-risk countries were moderate. Increases in incidence ranged from 25%-114%, 24%-55% and 15%-104% in high-, medium- and low-risk countries, respectively. Mortality rates rose more rapidly in Asian countries than in high-risk countries. Substantial differences in incidence and mortality across countries were evident, with U.S. blacks having rates that were 50-60 times higher than the rates in Shanghai, China. Increasing incidence rates in the United States and Canada are likely to be due in part to the widespread use of transurethral resection of the prostate and prostate-specific antigen testing, while increases in the Asian countries are probably related to westernization in these low-risk populations. The large disparities in incidence between high- and low-risk countries may be due to a combination of genetic and environmental factors. Future studies are needed to examine gene-gene and gene-environment interactions in various countries concurrently to shed light on the etiology of prostate cancer and to help elucidate reasons for the large differences in risk between populations. Copyright 2000 Wiley-Liss, Inc.
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              Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome.

              TMPRSS2:ERG gene fusions and PTEN deletions are the most common genomic aberrations in prostate cancer. Recent work has suggested that the TMPRSS2:ERG fusion is associated with a more aggressive phenotype. Similarly, PTEN deletion has been associated with biochemical recurrence and lymph node metastasis. To date, there has been no systematic analysis of the combined influence of genomic PTEN deletion with TMPRSS2:ERG gene fusions on clinical parameters of prostate cancer progression. We carried out a retrospective analysis of 125 prostate cancers with known clinical outcome using interphase fluorescence in situ hybridization to detect the relative prevalence of TMPRSS2:ERG rearrangements and/or PTEN genomic deletions. TMPRSS2:ERG rearrangement was found in 60 of 125 (48%) prostate cancers. Duplication of TMPRSS2:ERG fusion was observed in seven (6%) tumors. Gleason grade (P=0.0002)/score (P=0.001), median tumor volume (P=0.0024), preoperative PSA (P=0.001) and perineural invasion (P=0.0304) were significantly associated with biochemical recurrence by univariate analysis with TMPRSS2:ERG approaching significance (P=0.0523). By multivariate analysis, relevant factors associated with recurrence were Gleason scores 7 (P=0.001) and 8-10 (P=0.015), PTEN homozygous deletion (P=0.013) and concurrent TMPRSS2:ERG fusion and PTEN deletion (P=0.036). Kaplan-Meier analysis indicated that the presence of TMPRSS2:ERG fusion was marginally less favorable in comparison to no fusion. Duplication of fusion gene showed worse prognosis. It was possible to determine the relative frequencies of PTEN deletion and/or TMPRSS2:ERG fusions in 82 of 125 prostate cancers. With biochemical recurrence as an endpoint, the genomic biomarkers identified three patient groups: (1) 'poor genomic grade' characterized by both PTEN deletion and TMPRSS2:ERG fusions (23/82, 28%); (2) 'intermediate genomic grade' with either PTEN deletion or TMPRSS2:ERG fusion (35/82, 43%) and (3) 'favorable genomic grade' in which neither rearrangement was present (24/82, 29%). Kaplan-Meier and multivariate analysis indicate that TMPRSS2:ERG fusion and PTEN loss together are a predictor of earlier biochemical recurrence of disease.
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                Author and article information

                Contributors
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central
                1756-8722
                2014
                7 March 2014
                : 7
                : 21
                Affiliations
                [1 ]Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, Canada
                [2 ]Departments of Oncology, Biochemistry and Molecular Biology, Calgary, AB, Canada
                [3 ]Southern Alberta Cancer Institute and Tom Baker Cancer Center, Calgary, AB, Canada
                [4 ]The Prostate Cancer Center, Calgary, AB, Canada
                [5 ]Department of Urology, University of Calgary, Calgary, AB, Canada
                [6 ]Department of Pathology and Laboratory Medicine, Jordan University of Science and Technology, Irbid, Jordan
                Article
                1756-8722-7-21
                10.1186/1756-8722-7-21
                3975646
                24606912
                24e8f764-27c8-4fd8-a4da-cefceb0daad7
                Copyright © 2014 Al Bashir et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 16 January 2014
                : 3 March 2014
                Categories
                Research

                Oncology & Radiotherapy
                crisp3,erg,pten,biological pathways,prostate cancer,poorest outcome,molecular subtypes

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