Journal articles: 'Fusion TMPRSS2:ERG'

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Sung, Ji-Youn, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Moo Lee, Han Yong Choi, So Young Kang, Yoon-La Choi, and Ghee Young Kwon. "Correlation of ERG immunohistochemistry with molecular detection of TMPRSS2-ERG gene fusion." Journal of Clinical Pathology 69, no. 7 (December 15, 2015): 586–92. http://dx.doi.org/10.1136/jclinpath-2015-203314.

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AimsTMPRSS2/E26 transformation-specific (ETS) family gene fusion in prostate carcinoma (PCa) can be detected by several methods including immunohistochemistry (IHC) for ETS-related gene (ERG), the diagnostic utility of which has not been clearly defined.MethodsWe explored TMPRSS2-ERG gene rearrangement status in 132 patients with PCa with four detection methods including fluorescence in situ hybridisation for TMPRSS2-ERG fusion, real-time reverse transcription PCR (RT-qPCR) for ERG and TMPRSS-ERG fusion transcript mRNA and IHC for ERG.ResultsConcordant results were found in 126 cases for the four detection methods and the remaining six cases showed discrepancy in one method: two cases in IHC, three cases in RT-qPCR for ERG and one case in RT-qPCR for fusion transcript. In discordant cases, the majority results were determined as final fusion status. Analysis of discrepancy cases for ERG IHC showed that weak immunoreactivity for ERG should be regarded as equivocal and that even strong immunoreactivity can be false positive. The overall incidence of TMPRSS-ERG gene fusion was 24%.ConclusionsERG IHC is a useful surrogate test for the detection of TMPRSS2-ERG gene fusion, but it needs to be interpreted with caution and definite judgement should not be based on IHC alone. A relatively low incidence of TMPRSS2-ERG gene fusion was demonstrated in this Korean cohort.

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He, Wei, Fukang Sun, Juping Zhao, Dai Jun, Le Xu, Chenghe Wang, Chen Fang, et al. "Prevalence and genetic features of TMPRSS2-ERG fusion in Chinese patients with prostate cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e17529-e17529. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e17529.

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e17529 Background: Prostate cancer (PCa) is one of the most common malignancies, with rising incidence rate in China. The Cancer Genome Atlas (TCGA) revealed 53% of patients with PCa had ETS family gene fusions. The most frequent fusion type of ETS fusions is TMPRSS2-ERG, which may predicts resistance to taxane and androgen-deprivation therapies. The prevalence of TMPRSS2-ERG fusion in Chinese PCa patients evaluated by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) varied from 7.5% to 78.0%. However, the sample sizes were small. In the present study, we investigated the prevalence and genetic features of TMPRSS2-ERG fusion by next generation sequencing (NGS) in a larger Chinese PCa cohort. Methods: Genomic profiling was performed through NGS from Chinese patients with PCa between January, 2017 and November, 2019. Formalin fixed paraffin-embedded (FFPE) tumor specimens or blood samples from participants were collected for NGS. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay or Ventana PD-L1 SP263 assay. Data analyses were performed using SPSS and R 3.6.1. Results: A total of 526 Chinese PCa patients were included in this study. The median age was 70 (range, 29-90) years old. We observed 13.1% patients with a positive PD-L1 expression, 3.0% patients with MSI-H, and a median TMB of 4.0 muts/Mb (range: 0-72.9). TMPRSS2 fusions were detected in 47 (8.9%) PCa patients, and 6.8% of patients had TMPRSS2-ERG fusion, which is significantly lower than that of Caucasian patients. The PD-L1 expression pattern and TMB distribution of the TMPRSS2-ERG fusion-positive patients were similar with TMPRSS2-ERG fusion-negative patients, however no fusion-positive patients were identified as MSI-H. Among these 36 TMPRSS2-ERG fusion-positive patients, the most frequently somatic mutations were detected in TP53 (38.9%), AR (11.1%), ATM (11.1%), and PTEN (11.1%). 9 (22.2%) patients harbored somatic mutations in PI3K/ AKT/mTOR pathway that has been previously demonstrated to collaborate with ERG to promote prostate cancer progression. Conclusions: This study revealed the prevalence and genetic features of TMPRSS2-ERG fusion in Chinese PCa patients by NGS in the first time. Our results provide a better understanding of molecular features in Chinese TMPRSS2-ERG fusion-positive PCa patients.

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Minner, S., A. Krohn, L. Burkhardt, P. Tennstedt, R. Simon, H. Sirma, H. Huland, G. Sauter, and T. Schlomm. "Chromosomal deletions, tumor phenotype, and prognosis in prostate cancer." Journal of Clinical Oncology 29, no. 7_suppl (March 1, 2011): 37. http://dx.doi.org/10.1200/jco.2011.29.7_suppl.37.

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37 Background: Chromosomal deletions are frequent in prostate cancer (PCa) but target genes and potential clinical significance are often unknown. This project aimed at the identification of frequent and new deletions in PCa and to study their association with tumor phenotype and PSA recurrence. Methods: Array CGH was performed on 77 advanced PCa. Deletions of interest were subsequently analyzed on a tissue microarray containing more than 2000 PCa with clinical follow-up data using fluorescence in situ hybridization (FISH). The FISH probes used included a break-apart probe for TMPRSS2-ERG and dual-labeling probes for centromere 10/PTEN and centromere 3/3p14. Results: The most frequent circumscribed deletions found by array CGH were 3p14 (including FOXP1) in 18%, 5q31 in 16%, 5q21 in 14%, 6q13 in 21%, 6q21 in 19%, 6q26 in 14%, 8p11 in 17%, 10q23 (including PTEN) in 18%, 12p13 in 14%, 13q14 in 14%, 16q24 in 22% and 21q (representing TMPRSS2-ERG fusion) in 18%. TMPRSS2-ERG fusions, PTEN and FOXP1 deletions were selected for FISH analysis. A TMPRSS2-ERG fusion was observed in 394 of 947 interpretable cases (41.6%). TMPRSS2-ERG fusion was unrelated to tumor stage, Gleason grade, and PSA recurrence. PTEN deletions were observed in 8.9% of 1844 interpretable cases and were associated with advanced tumor stage (p<0.0001), high Gleason grade (p<0.0001), and early biochemical recurrence (p<0.0001). FOXP1 deletions were seen in 5.0% of 619 cases. FOXP1 deletions were not significantly linked to tumor phenotype and outcome. Both PTEN and FOXP1 deletions were strongly linked to TMPRSS2-ERG fusions. TMPRSS2-ERG fusion positive tumors had PTEN deletions in 15.4% and FOXP1 deletions in 10.7%, while TMPRSS2-ERG fusion negative cancers had PTEN deletions in only 5.8% and FOXP1 deletions in only 2.0% of cases (p<0.0001 each). Conclusions: The TMPRSS2-ERG fusion determines a genetically distinct subgroup of prostate cancers. Our data provide no evidence for a particular clinical behaviour of TMPRSS2-ERG fusion positive cancers in radically operated patients. PTEN and FOXP1 alterations are preferentially found in TMPRSS2-ERG fusion positive cancers. Both genes may potentially be involved in pathway dysregulation in these cancers. No significant financial relationships to disclose.

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Yoshimoto, M., A. M. Joshua, S. Chilton-Macneill, J. Bayani, M. Prasad, N. Fleshner, A. Finelli, et al. "Detection of novel variant TMPRSS2 /ERG fusion transcripts suggests independent genomic alterations may underlie origin of multi-centric prostate cancer." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 10029. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10029.

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10029 Background: Most of the early successes in identifying chromosomal translocations in neoplasias came from the study of hematological malignancies and sarcomas, with limited evidence that consistent genomic rearrangements were present in epithelial malignancies. Recently it was reported that ∼75% of prostate cancers carry a genomic rearrangement leading to fusion of the TMPRSS2 locus to either the ERG or ETV1 genes (both ETS transcription factors). In the fusion gene, the androgen-sensitive promoter elements of TMPRSS2 are thought to mediate over-expression of these ETS transcription factors. Over-activity of the ETS family of transcription factors has been suggested to be involved in the transition from pre-neoplasia to carcinoma as they regulate genes involved in processes such as adhesion, motility, invasion and angiogenesis. Methods: Using both RT-PCR and FISH with published primers and BACs respectively we analyzed 15 samples of prostatic carcinoma from radical prostatectomies and sequenced a subset of the TMPRSS2/ERG fusions. Results: We have found ERG-TMPRSS2 fusion transcripts in 6 samples and no ETV1-TMPRSS2 fusions. Of the 6 fusion tumours, 5 were Gleason 7 and 1 was Gleason 9. Tumour stages ranged from T2a-T3b. One sample with multi-centric carcinoma exhibited 2 distinct in-frame rearrangements generating novel TMPRSS2 /ERG fusion transcripts. Variant I TMPRSS2/ERG transcript was 430 bp and it led to fusion of exons 1 and 2 of the TMPRSS2 gene with exons 5 and 6 of the ERG gene. Variant II TMPRSS2/ERG fusion transcript was slightly smaller at 350 bp and it led to fusion of exon 1 of the TMPRSS2 gene to exons 5 and 6 of the ERG gene. These novel transcripts appear to be smaller than the published fusion proteins but preliminary analysis suggests that all known regulatory and functional protein domains are maintained. Conclusions: The demonstration of two new TMPRSS2/ERG variant fusion transcripts in prostate cancer deserves further study to evaluate their functional impact and prognostic and pathological importance. Moreover the presence of two distinct transcripts within a single multi-centric tumor provides genomic evidence that independent clonal neoplasms can arise synchronously in prostate cancer. No significant financial relationships to disclose.

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Lara, Primo N., Andreas M. Heilmann, Julia A. Elvin, Mamta Parikh, Ralph de Vere White, Regina Gandour-Edwards, Christopher P. Evans, et al. "TMPRSS2-ERG Fusions Unexpectedly Identified in Men Initially Diagnosed With Nonprostatic Malignancies." JCO Precision Oncology, no. 1 (November 2017): 1–6. http://dx.doi.org/10.1200/po.17.00065.

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Purpose TMPRSS2-ERG gene fusions are frequently found in prostate cancer and are pathognomonic for prostatic origin. In a series of cancer cases assayed with comprehensive genomic profiling (CGP) in the course of clinical care, we reviewed the frequency of TMPRSS2-ERG fusions in patient tumors of various histologic subtypes. Methods Frequency of TMPRSS2-ERG fusions was determined in CGPs from 64,263 cancer cases submitted to Foundation Medicine to assess genomic alterations suggesting benefit from targeted therapy. Genomic results are presented from an index case of prostate cancer that underwent evolution from adenocarcinoma to pure squamous cell carcinoma. Results TMPRSS2-ERG fusions were identified for 0.86% of male patients (250 of 29,030) and not found for female patients (none of 35,233). TMPRSS2-ERG fusions were detected in six tumors classified as squamous carcinoma, five of which were of unknown primary site. The index case is a patient with a large, left retrovesical mass diagnosed as squamous carcinoma by morphologic examination and a history of Gleason score 9 prostate cancer with prior prostatectomy and salvage radiation therapy. TMPRSS2-ERG was detected by genomic profiling in the squamous cell tumor, the primary adenocarcinoma of the prostate, and in a metachronous prostatic adenocarcinoma metastasis. On the basis of these results, the patient received androgen deprivation therapy. A phylogenetic tree demonstrating clonal and histopathologic evolution of prostate cancer in the index patient was constructed. Conclusion In this large CGP dataset, TMPRSS2-ERG fusion was seen in approximately 30% of prostate cancers regardless of histologic type; on occasion, the fusion was detected in advanced cancers not initially carrying a diagnosis of prostate carcinoma. CGP of advanced cancers in men may reveal prostatic origin by detection of the pathognomonic TMPRSS2-ERG fusion gene.

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Mani, Ram-Shankar, Scott A. Tomlins, Kaitlin Callahan, Aparna Ghosh, Mukesh K. Nyati, Sooryanarayana Varambally, Nallasivam Palanisamy, and Arul M. Chinnaiyan. "Induced Chromosomal Proximity and Gene Fusions in Prostate Cancer." Science 326, no. 5957 (October 29, 2009): 1230. http://dx.doi.org/10.1126/science.1178124.

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Gene fusions play a critical role in cancer progression. The mechanisms underlying their genesis and cell type specificity are not well understood. About 50% of human prostate cancers display a gene fusion involving the 5′ untranslated region of TMPRSS2, an androgen-regulated gene, and the protein-coding sequences of ERG, which encodes an erythroblast transformation–specific (ETS) transcription factor. By studying human prostate cancer cells with fluorescence in situ hybridization, we show that androgen signaling induces proximity of the TMPRSS2 and ERG genomic loci, both located on chromosome 21q22.2. Subsequent exposure of the cells to gamma irradiation, which causes DNA double-strand breaks, facilitates the formation of the TMPRSS2-ERG gene fusion. These results may help explain why TMPRSS2-ERG fusions are restricted to the prostate, which is dependent on androgen signaling.

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KULDA, VLASTIMIL, ONDREJ TOPOLCAN, RADEK KUCERA, MICHAELA KRIPNEROVA, KRISTYNA SRBECKA, MILAN HORA, ONDREJ HES, et al. "Prognostic Significance of TMPRSS2-ERG Fusion Gene in Prostate Cancer." Anticancer Research 36, no. 9 (September 9, 2016): 4787–94. http://dx.doi.org/10.21873/anticanres.11037.

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Trifunovski, Aleksandar, Aleksandar Dimovski, Sasho Dohcev, Sotir Stavridis, Oliver Stankov, Skender Saidi, Marija Gjorgjievska, and Zivko Popov. "Detection of TMPRSS2-ERG Fusion Transcript in Biopsy Specimen of Prostate Cancer Patients: A Single Centre Experience." PRILOZI 41, no. 1 (June 1, 2020): 5–14. http://dx.doi.org/10.2478/prilozi-2020-0018.

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AbstractIntroduction: Prostate carcinoma is the most frequent malign neoplasm among men with an ever-growing incidence rate. TMPRSS2-ERG fusion transcript leads to the androgen induction of ERG proto-oncogenes expression, representing a high presence of oncogenes alteration among prostate tumour cells.Aim: The aim of this research was to detect and evaluate theTMPRSS2-ERG fuse transcript in the tissues of patients with prostate cancer, and establish a base of material of these samples for further genetic examination.Materials and methods: The research was a prospective clinical study that involved and focused on random sampling of 101 patients (62 with prostate cancer-study group and 39 with benign changes in the prostate-control group). Real time PCR analysis for detection of the TMPRSS2-ERG fusion transcript in prostate tissue was performed and also data from the histopathology results of tissues were used, as well as data for the level of PSA (prostate-specific antigen) in blood.Results: TMPRSS2-ERG fusion transcript was detected in 20 out of 62 (32.2%) patients with prostate carcinoma and among no patients with benign changes whatsoever. There were no significant differences between patients with/without detected TMPRSS2-ERG fusion related to Gleason score. Among 50%, in the study group this score was greater than 7 per/for Median IQR=7 (6-8). Significant difference was recognized, related to the average value of PSA in favour of significantly higher value of PSA in the study group with prostate cancer, but there was also no significant difference between samples with prostate cancer who were with/without detected TMPRSS2-ERG fusion transcript related to PSA level.Discussion: The results from this research are in accordance with the values and results from analyses done in several research centres and oncological institutes.Conclusion: The positive findings in small scale studies encourage the implementation of larger scale studies that will be enriched with results of genetic transcript in blood and urine and will define the positive diagnostic meaning of the TMPRSS-ERG fusion transcript.

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Dal Pra, Alan, Fiona Warde, Adrian Shea Ishkanian, Alice Meng, Chad Malloff, Wan Lam, Jenna Sykes, et al. "TMPRSS2-ERG status and biochemical recurrence following radiotherapy for intermediate-risk prostate cancer." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 11. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.11.

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11 Background: Approximately 50% of prostate cancers (PC) contain TMPRSS2-ERG gene fusions leading to ERG overexpression. Pre-clinical data suggest that these fusions are due to altered DNA double-strand break repair status which could have therapeutic ramification for the use of radiotherapy (RT) and PARP inhibitors. The aim of this study was to correlate TMPRSS2-ERG status to biochemical failure following clinical induction of DNA breaks in the form of image-guided radiotherapy (IGRT) in intermediate-risk PC. Methods: Pre-treatment biopsies from two separate cohorts of intermediate-risk PC patients (T1/T2, GS < 8, PSA < 20ng/ml) were analyzed: 1) 126 patients assessed by array Comparative Genomic Hybridization (aCGH) for TMPRSS2:ERG fusion; and 2) 121 patients assessed by tissue microarray (TMA) for ERG expression by immunohistochemistry (IHC). All patients received IGRT with a median dose of 79.8 Gy (60-79.8 Gy). TMPRSS2:ERG status was correlated to Gleason score, T stage, initial PSA and biochemical-free relapse rate (bFRR; Phoenix definition: nadir + 2ng/ml). Results: At a median follow-up time of 6.36 years, the biochemical relapse event rate was 37% and 18% in the aCGH and IHC cohorts, respectively. ERG expression by IHC was found in 49.6% of the 121 PC. TMPRSS2-ERG status was not correlated to increased Gleason score, pre-treatment PSA or T stage. On multivariate analyses in models containing clinical factors, TMPRSS2:ERG status (either using aCGH or IHC) was not prognostic for biochemical outcome (ERG expression: HR=0.78, 95% CI: 0.33-1.85; p= 0.568; TMPRSS2-ERG fusion: HR=0.71, 95% CI: 0.35-1.41; p=0.326). Conclusions: In two separate cohorts, TMPRSS2-ERG status was not prognostic for bRFR after IGRT. Although a trend was observed, these clinical data do not support the hypothesis that these cancers have DNA repair defects that render them significantly more radiosensitive when compared to other PC. Further clinical trials are required to understand the utility of TMPRSS2:ERG status and response to DNA damaging agents, including that of PARP inhibitors. The trans-Canadian PROFIT trial is completing accrual of close to 1200 patients allowing for TMPRSS2:ERG studies in a larger RT cohort.

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Klein, E. A., S. M. Falzarano, T. Maddala, D. Cherbavaz, W. F. Novotny, C. Millward, and C. Magi-Galluzzi. "Use of TMPRSS2-ERG gene rearrangement and quantitative ERG expression to predict clinical recurrence after radical prostatectomy." Journal of Clinical Oncology 29, no. 7_suppl (March 1, 2011): 36. http://dx.doi.org/10.1200/jco.2011.29.7_suppl.36.

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36 Background: The association of TMPRSS2-ERG fusions and ERG expression in prostate cancer (PC) with adverse clinical outcomes has been controversial, with mixed results in the literature. We conducted a study to test whether tumor-derived gene expression profiles, including the presence of TMPRSS2-ERG fusions and ERG gene expression, are associated with clinical recurrence (cR) after radical prostatectomy (RP). Methods: All patients with clinical stage T1/T2 prostate cancer treated with RP at CC from 1987 to 2004 were identified (n∼f2,600). A cohort sampling design was used to select 127 patients with cR and 374 patients without cR after RP. For each patient a primary Gleason pattern (GP) sample, secondary (or highest) GP sample, and an adjacent nontumor tissue sample were evaluated. Surgical Gleason Score (GS) and clinical data were centrally reviewed. RNA was extracted from 6 manually dissected 10 μ m formalin-fixed paraffin-embedded sections obtained from RP specimens and expression of TMPRSS2-ERGa, TMPRSS2-ERGb, ERG and reference genes were quantified using RT-PCR. Times to cR, PSA recurrence, and PC death were analyzed using Cox PH regression. Results: Blocks from 441 patients were evaluable. Median F/U was 5.8 years. Patients were mostly Caucasian (83%), clinical stage T1 (66%), had baseline PSA <10 ng/mL (82%), and had surgical Gleason score ≤7 (87%). 848 tumor samples and 410 non-tumor samples were assessed. TMPRSS2-ERGa and/or TMPRSS2-ERGb fusions were present in 51.8% of tumor samples and 7.5% of non-tumor samples. There was 89% concordance (95% CI: 86%, 92%) for TMPRSS2-ERG fusion status between the 2 tumor samples for each patient. High ERG expression was strongly associated with the presence of TMPRSS2-ERG fusions (p <0.01). We did not find an association between TMPRSS2-ERG a/b gene rearrangement or ERG expression with cR, PSA recurrence, PC death, or surgical GS (p > 0.2). Conclusions: This study was notable for the large number of cR events, use of a standardized quantitative assay, and rigorous central review of pathology and clinical data. We did not find an association of TMPRSS2-ERG gene rearrangements or ERG expression with aggressiveness of prostate cancer post RP. [Table: see text]

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Graff, Rebecca E., Allison Meisner, Thomas Ahearn, Michelangelo Fiorentino, Howard D. Sesso, Edward L. Giovannucci, Lorelei A. Mucci, and Andreas Pettersson. "Pre-diagnostic circulating sex hormone levels and risk of prostate cancer by TMPRSS2:ERG status." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 93. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.93.

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93 Background: Experimental studies have shown that androgen receptor stimulation can facilitate formation of the TMPRSS2:ERG gene fusion in prostate cell lines. No study has tested whether higher pre-diagnostic circulating sex hormone levels in men increase the risk of developing TMPRSS2:ERG positive prostate cancer specifically. Methods: We conducted a nested case-control study of 200 prostate cancer cases and 1,057 controls from the Physicians’ Health Study and Health Professionals Follow-up Study. We examined associations between pre-diagnostic circulating levels of total testosterone, free testosterone, DHT, androstanediol glucuronide, estradiol, and SHBG and risk of prostate cancer by TMPRSS2:ERG status. TMPRSS2:ERG was assessed by ERG immunohistochemistry. We used multivariable unconditional polytomous logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of fusion-positive (n = 94) and, separately, fusion-negative (n = 106) disease. Results: Free testosterone was significantly associated with the risk of ERG-positive prostate cancer (OR: 1.37, 95% CI: 1.05-1.77), but not ERG-negative prostate cancer (OR: 1.09, 95% CI: 0.86-1.38) (p-diff: 0.17). None of the remaining hormones evaluated showed clear differential associations with ERG-positive versus ERG-negative disease. Conclusions: These findings provide some suggestive evidence that higher pre-diagnostic free testosterone levels are associated with an increased risk of developing TMPRSS2:ERG positive prostate cancer but are not associated with prostate cancer that lacks TMPRSS2:ERG.

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Knuuttila, Matias, Arfa Mehmood, Jenni Mäki-Jouppila, Henrik Ryberg, Pekka Taimen, Juha Knaapila, Otto Ettala, et al. "Intratumoral androgen levels are linked to TMPRSS2-ERG fusion in prostate cancer." Endocrine-Related Cancer 25, no. 9 (September 2018): 807–19. http://dx.doi.org/10.1530/erc-18-0148.

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Intratumoral androgen biosynthesis is one of the mechanisms involved in the progression of prostate cancer, and an important target for novel prostate cancer therapies. Using gas chromatography-tandem mass spectrometry and genome-wide RNA sequencing, we have analyzed androgen concentrations and androgen-regulated gene expression in cancerous and morphologically benign prostate tissue specimens and serum samples obtained from 48 primary prostate cancer patients. Intratumoral dihydrotestosterone (DHT) concentrations were significantly higher in the cancerous tissues compared to benign prostate (P < 0.001). The tissue/serum ratios of androgens were highly variable between the patients, indicating individual patterns of androgen metabolism and/or uptake of androgens within the prostate tissue. An unsupervised hierarchical clustering analysis of intratissue androgen concentrations indicated that transmembrane protease, serine 2/ETS-related gene (TMPRSS2-ERG)-positive patients have different androgen profiles compared to TMPRSS2-ERG-negative patients. TMPRSS2-ERG gene fusion status was also associated with an enhanced androgen-regulated gene expression, along with altered intratumoral androgen metabolism, demonstrated by reduced testosterone concentrations and increased DHT/testosterone ratios in TMPRSS2-ERG-positive tumors. TMPRSS2-ERG-positive and -negative prostate cancer specimens have distinct intratumoral androgen profiles, possibly due to activation of testosterone-independent DHT biosynthesis via the alternative pathway in TMPRSS2-ERG-positive tumors. Thus, patients with TMPRSS2-ERG-positive prostate cancer may benefit from novel inhibitors targeting the alternative DHT biosynthesis.

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Giunchi, Francesca, Francesco Massari, Annalisa Altimari, Elisa Gruppioni, Elisabetta Nobili, Michelangelo Fiorentino, and Andrea Ardizzoni. "Dual TMPRSS2:ERG Fusion in a Patient with Lung and Prostate Cancers." Diagnostics 10, no. 12 (December 20, 2020): 1109. http://dx.doi.org/10.3390/diagnostics10121109.

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The TMPRSS2:ERG fusion is considered prostate specific and has been rarely described in other tumors. We describe the case of a patient who developed lung and prostate cancers, both harboring the TMPRSS2:ERG fusion. The patient developed a cancer of the prostate with lymph node metastases and after two years a nodule of the thoracic wall. The histology and immunohistochemical profile of the two tumors were typical of prostate and lung cancers. The presence of the TMPRSS2:ERG fusion was demonstrated by next-generation sequencing on both malignancies, leading to the assumption that the lung nodule was a metastasis from the prostate cancer. The patient failed to respond to antiandrogen therapy, while chemotherapy for lung cancer led to a significant objective response. To our knowledge, this is the first case of a lung cancer harboring the TMPRSS2:ERG fusion, widening the spectrum of lung cancer-associated molecular alterations.

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Mao, Xueying, Nuria Coll Bastus, Lara Boyd, Yongwei Yu, Guoping Ren, Luis Beltran, R. Oliver, Bryan D. Young, Dan Berney, and Yong-Jie Lu. "The different genetic alterations between Western and Chinese prostate cancers and the underlying mechanisms." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 184. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.184.

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184 Background: Prostate cancer shows a wide variation in the clinical incidence and mortality rates of different geographical regions. While it is the most common male cancer in Western countries, it is much less frequent in Asian countries. We investigated genomic changes in prostate cancers from UK and China using microarrays to determine the genetic similarities and differences as well as the underlying mechanisms. Methods: We determined genome-wide genomic alterations using Affymetrix SNP array 6.0, and evaluated data using fluorescence in situ hybridisation (FISH) and immunohistochemistry. In addition, we assess androgen induced TMPRSS2 and ERG co-localization and fusion. Microsatellite analysis was used for AR CAG repeat polymorphism in UK and Chinese population. Results: Genome-wide analysis of 32 UK and 39 Chinese samples revealed that losses of 21q22 (leading to TMPRSS2:ERG fusion) and 10q23.3 (PTEN) were at much higher frequency in Western than Chinese prostate cancers. Using FISH analysis of 160 UK and 143 Chinese samples, we showed that PTEN deletion and ERG rearrangements were at a significantly higher frequency in samples from UK than China (p<0.001 for both). We found that PTEN and ERG protein were also differentially expressed (p<0.001) in the two populations. Investigating this further, we induced TMPRSS2 and ERG gene proximity and TMPRSS2:ERG fusion in two immortalised prostate epithelial cell lines by exposure to high dose of androgen. This androgen treatment did not cause increased global DNA damage but was associated with low expression of PIWIL1, which is involved in repairing double-strand breaks. Overexpression of PIWIL1 by transfection inhibited androgen induced TMPRSS2:ERG fusion. We found that AR CAG repeat lengths, which associated with AR activity, are significantly shorter in the UK than Chinese patients (p<0.05). Conclusions: We revealed genomic differences in prostate cancer comparing the high-risk (Western) and low-risk (Chinese) populations. We further demonstrated that TMPRSS2:ERG fusion can be induced by androgen. The difference of CAG repeat length between the two populations are potentially associated with TMPRSS2:ERG fusion positive prostate cancers.

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Gerashchenko, G. V., L. V. Mevs, L. I. Chashchina, M. V. Pikul, O. P. Gryzodub, E. O. Stakhovsky, and V. I. Kashuba. "EXPRESSION OF STEROID AND PEPTIDE HORMONE RECEPTORS, METABOLIC ENZYMES AND EMT-RELATED GENES IN PROSTATE TUMORS IN RELATION TO THE PRESENCE OF THE TMPRSS2/ERG FUSION." Experimental Oncology 40, no. 2 (June 22, 2018): 101–8. http://dx.doi.org/10.31768/2312-8852.2018.40(2):101-108.

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Aim: To analyze an expression pattern of the steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes in prostate tumors in relation to the presence of the TMPRSS2/ERG fusion; and to examine a putative correlation between gene expression and clinical characteristics, to define the molecular subtypes of prostate cancer. Materials and Methods: The relative gene expression (RE) of 33 transcripts (27 genes) and the presence/absence of the TMPRSS2/ERG fusion were analyzed by a quantitative PCR. 37 prostate cancer tissues (T) paired with conventionally normal prostate tissue (CNT) and 21 samples of prostate adenomas were investigated. RE changes were calculated, using different protocols of statistics. Results: We demonstrated differences in RE of seven genes between tumors and CNT, as was calculated, using the 2−ΔCT model and the Wilcoxon matched paired test. Five genes (ESR1, KRT18, MKI67, MMP9, PCA3) showed altered expression in adenocarcinomas, in which the TMPRSS2/ERG fusion was detected. Two genes (INSR, isoform B and HOTAIR) expressed differently in tumors without fusion. Comparison of the gene expression pattern in adenomas, CNT and adenocarcinomas demonstrated that in adenocarcinomas, bearing the TMPRSS2/ ERG fusion, genes KRT18, PCA3, and SCHLAP1 expressed differently. At the same time, we detected differences in RE of AR (isoform 2), MMP9, PRLR and HOTAIR in adenocarcinomas without the TMPRSS2/ERG fusion. Two genes (ESR1 and SRD5A2) showed differences in RE in both adenocarcinoma groups. Fourteen genes, namely AR (isoforms 1 and 2), CDH1, OCLN, NKX3-1, XIAP, GCR (ins AG), INSR (isoform A), IGF1R, IGF1R tr, PRLR, PRL, VDR and SRD5A2 showed correlation between RE and tumor stage. RE of four genes (CDH2, ESR2, VDR and SRD5A2) correlated with differentiation status of tumors (Gleason score). Using the K-means clustering, we could cluster adenocarcinomas in three groups, according to gene expression profiles. A specific subtype of prostate tumors is characterized by the activated ERG signaling, due to the presence of TMPRSS2/ERG fusion, and also by high levels of the androgen receptor, prolactin, IGF, INSR and PCA3. Conclusions: We have found the specific differences in expression of the steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes, depending on the presence/absence of the TMPRSS2/ERG fusion in prostate adenocarcinomas, CNT and adenomas. We showed three different gene expression profiles of prostate adenocarcinomas. One of them is characteristic for adenocarcinomas with the TMPRSS2/ERG fusion. Further experiments are needed to confirm these data in a larger cohort of patients.

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Burdova, Alena, Jan Bouchal, Spiros Tavandzis, and Zdenek Kolar. "TMPRSS2-ERG gene fusion in prostate cancer." Biomedical Papers 158, no. 4 (December 9, 2014): 502–10. http://dx.doi.org/10.5507/bp.2014.065.

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Washington, Michele N., and Nancy L. Weigel. "1α,25-Dihydroxyvitamin D3 Inhibits Growth of VCaP Prostate Cancer Cells Despite Inducing the Growth-Promoting TMPRSS2:ERG Gene Fusion." Endocrinology 151, no. 4 (February 10, 2010): 1409–17. http://dx.doi.org/10.1210/en.2009-0991.

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Vitamin D receptor (VDR) agonists have been shown to reduce the growth of several prostate cancer cell lines. However, the effects of VDR activation have not been examined in the presence of the recently identified androgen-regulated TMPRSS2:ERG gene fusions, which occur in a high percentage of prostate cancers and play a role in growth and invasiveness. In a previous microarray study, we found that VDR activation induces TMPRSS2 expression in LNCaP prostate cancer cells. Here we show that the natural VDR agonist 1α,25-dihydroxyvitamin D3 and its synthetic analog EB1089 increase expression of TMPRSS2:ERG mRNA in VCaP prostate cancer cells; this results in increased ETS-related gene (ERG) protein expression and ERG activity as demonstrated by an increase in the ERG target gene CACNA1D. In VCaP cells, we were not able to prevent EB1089-mediated TMPRSS2:ERG induction with an androgen receptor antagonist, Casodex, although in LNCaP cells, as reported for some other common androgen receptor and VDR target genes, Casodex reduces EB1089-mediated induction of TMPRSS2. However, despite inducing the fusion gene, VDR agonists reduce VCaP cell growth and expression of the ERG target gene c-Myc, a critical factor in VDR-mediated growth inhibition. Thus, the beneficial effects of VDR agonist treatment override some of the negative effects of ERG induction, although others remain to be tested.

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Clark, Jarrod P., Kristofer W. Munson, Jessie W. Gu, Katarzyna Lamparska-Kupsik, Kevin G. Chan, Jeffrey S. Yoshida, Mark H. Kawachi, et al. "Performance of a Single Assay for Both Type III and Type VI TMPRSS2:ERG Fusions in Noninvasive Prediction of Prostate Biopsy Outcome." Clinical Chemistry 54, no. 12 (December 1, 2008): 2007–17. http://dx.doi.org/10.1373/clinchem.2008.108845.

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Abstract Background: TMPRSS2:ERG fusions are promising prostate cancer biomarkers. Because they can occur in multiple forms in a single cancer specimen, we developed a quantitative PCR test that detects both type III and type VI TMPRSS2:ERG fusions. The assay is quantified from a standard curve determined with a plasmid-cloned type III TMPRSS2:ERG fusion target. Methods: We collected expressed prostatic secretion (EPS) under an institutional review board-approved, blinded, prospective study from 74 patients undergoing transrectal ultrasound-guided biopsy for prostate cancer. We compared the characteristic performance of the test for type III and type VI TMPRSS2:ERG fusions in predicting biopsy outcome and distinguishing between high and low Gleason scores with similar tests for the expression of PCA3 and DNA methylation levels of the APC, RARB, RASSF1, and GSTP1 genes. We used logistic regression to analyze the effects of multiple biomarkers in linear combinations. Results: Each test provided a significant improvement in characteristic performance over baseline digital rectal examination (DRE) plus serum prostate-specific antigen (PSA); however, the test for type III and type VI TMPRSS2:ERG fusions yielded the best performance in predicting biopsy outcome [area under the curve (AUC) 0.823, 95% CI 0.728–0.919, P < 0.001] and Gleason grade >7 (AUC 0.844, 95% CI 0.740–0.948, P < 0.001). Conclusions: Although each test appears to have diagnostic value, PSA plus DRE plus type III and type VI TMPRSS2:ERG provided the best diagnostic performance in EPS specimens.

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Gasi Tandefelt, Delila, Joost Boormans, Karin Hermans, and Jan Trapman. "ETS fusion genes in prostate cancer." Endocrine-Related Cancer 21, no. 3 (March 20, 2014): R143—R152. http://dx.doi.org/10.1530/erc-13-0390.

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Prostate cancer is very common in elderly men in developed countries. Unravelling the molecular and biological processes that contribute to tumor development and progressive growth, including its heterogeneity, is a challenging task. The fusion of the genes ERG and TMPRSS2 is the most frequent genomic alteration in prostate cancer. ERG is an oncogene that encodes a member of the family of ETS transcription factors. At lower frequency, other members of this gene family are also rearranged and overexpressed in prostate cancer. TMPRSS2 is an androgen-regulated gene that is preferentially expressed in the prostate. Most of the less frequent ETS fusion partners are also androgen-regulated and prostate-specific. During the last few years, novel concepts of the process of gene fusion have emerged, and initial experimental results explaining the function of the ETS genes ERG and ETV1 in prostate cancer have been published. In this review, we focus on the most relevant ETS gene fusions and summarize the current knowledge of the role of ETS transcription factors in prostate cancer. Finally, we discuss the clinical relevance of TMRPSS2–ERG and other ETS gene fusions in prostate cancer.

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Russo, Leileata M., Kendall Bate, Piruz Motamedinia, Guillermo Salazar, Anna Scott, Michael Lipsky, Neda Sadeghi, et al. "Urinary exosomes as a stable source of mRNA for prostate cancer analysis." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 174. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.174.

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174 Background: Exosomes are novel lipid bilayer vesicles that are released into biofluids such as urine and carry high integrity RNA from the parent cell which they were derived. Due to their unique stability and the fact that they contain prostate specific mRNA transcripts, we examined their potential as a non-invasive source of mRNA biomarkers for prostate cancer analysis. Methods: Following a Columbia University approved IRB protocol, random urine samples were collected from 163 men who were stratified into 4 groups: biopsy negative (Bx Neg, n=39), biopsy positive (Bx Pos, n=47), post-radical prostatectomy (RP, n=37) and controls (males <35 yrs, n=40). Urine samples were stored at 4°C and 0.8 μm filtration was used to remove whole cells and debris. Urinary exosomal RNA was isolated using our in-house technique. RT-qPCR was used to analyze PSA, PCA3, androgen receptor (AR), survivin, NCOA2, RAD21, transmembrane protease serine 2 (TMPRSS2), ERG and TMPRSS2:ERG fusion at the mRNA level. Results: Mean serum PSA protein level and age were similar in the Bx Neg and Bx Pos groups. Relative quantitation (RQ) of genes standardized to the PSA gene revealed that ERG (P<0.005), PCA3 (P<0.005), TMPRSS2:ERG fusion (P<0.05), TMPRSS2 (P<0.05) and survivin (P<0.005) were significantly increased in the Bx Pos vs. Bx Neg group. TMPRSS2:ERG fusion events occurred in 68% of Bx Pos vs. 44% of Bx Neg patients and were present in only 5% of controls. No patient in the RP group had positive TMPRSS2:ERG detection; this finding was further supported by the loss of TMPRSS2:ERG expression for 4 Bx Pos patients following prostatectomy suggesting specificity of the fusion event to the prostate. Conclusions: This study confirms urinary exosomes as a source of high quality RNA and showed significant differences in the expression of ERG, PCA3, TMPRSS2:ERG genes between the Bx Pos and Bx Neg groups. Our findings are consistent with previous studies based on tissue and post-prostate massage urinary cell analyses. The unique stability and yield of urinary exosomal RNA collected without a prostatic massage will hopefully simplify sample handing, obviate sample variability and patient discomfort inherent to prostate massage, and broaden the role of exosomes in future diagnostic testing.

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Lu, Yong-Jie, Xiaoyan Liu, Xueying Mao, Lucy Hylands, Jeremy Clark, Colin Cooper, and Guoping Ren. "Truncation of BRAF and Raf1 in prostate cancer in China." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 77. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.77.

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77 Background: Chromosome translocations and fusion genes have been identified as common events in carcinomas in recent years and TMPRSS2:ERG fusions have been found in about half of human prostate cancers. However, by genome-wide analysis of Chinese prostate cancer cases, we found that certain genomic alterations, commonly identified in prostate cancer samples from the Western countries, occurred at a very low frequency in China, including the fusion of TMPRSS2:ERG. In 2010, recurrent fusion genes involving the RAF family gene BRAF and Raf1 were identified (Palanisamy et al, Nature Med. 16:793). Although the frequency of fusions involving BRAF and Raf1 are at a much lower frequency than fusion of TMPRSS2:ERG, BRAF and Raf1 are drugable, making them potential therapeutic targets. As the TMPRSS2:ERG fusion is infrequent in Chinese prostate cancers, we investigated if fusions involving BRAF and Raf1 occur at a higher frequency in prostate cancer in China than in Western countries. Methods: We used the fluorescence in situ hybridization signal split apart approach on prostate cancer samples made into tissue microarrays to detect the frequency of BRAF and Raf1 truncations. Three BAC probes on each side (5’ and 3’) of the two genes were labeled differentially using biotin and digoxigenin and subsequentially detected as red and green fluorescent signals, respectively. Results: We found that BRAF was truncated in four (two split signals, one 5’ deletions and one 3’ deletions) of the 193 informative cases (2.07%) and RAFaf1 (two 5’ deletions and one split signals) was truncated in three of 201 informative cases (1.49%). Although in some cases, three or four copies of these genes were detected, extensive copy number gain caused by amplification was not detected. Conclusions: These results indicate that truncations and potentially fusion of BRAF and Raf1 exist in Chinese prostate cancer, but at a similar low frequency as found in the Western samples (6/349 for BRAF and 4/450 for Raf1). Further studies are required to confirm the functional consequence of these truncations and to evaluate the therapeutic value of targeting these genes in this sub-group of prostate cancers.

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Grande, Enrique, Maria Piedad Fernandez Perez, Daniel Wetterskog, Albert Font Pous, Sergio Vazquez-Estevez, Aránzazu Gonzalez del Alba, Begona Mellado, et al. "A phase II multicenter biomarker trial to study the predictive value of TMPRSS2-ERG before enzalutamide treatment in chemo-naïve metastatic castration-resistant prostate cancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 5040. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5040.

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5040 Background: TMPRSS2-ERG fusion gene is a common driver of prostate cancer. The PREMIERE study is a phase II, single arm open-label, multicentre, clinical trial designed to analyse the predictive/prognostic value of TMPRSS2-ERG in first-line chemo-naïve mCRPC patients treated with enzalutamide. Methods: We centrally evaluated TMPRSS2-ERG in diagnostic samples using PCR, FISH and IHC for ERG. Among exploratory biomarkers we included plasma DNA, AR copy number by ddPCR and CTC by AdnaTest. PCWG2 criteria were used for outcome evaluation. We correlated TMPRSS2-ERGand other exploratory biomarkers with mCRPC outcomes. Results: Ninety eight patients with median age 77 y (range 59-95), ECOG 0/1 (54/46%) with mts located in bone (82%), LN (48%) and visceral (17%). With a median FU of 37.3 months, PSA response was PSA50: 82% and PSA90: 53%; median PSA-PFS was 13.7m (95%CI 10.2-19.0), Rad-PFS 26.7m (95%CI: 22.0-NA) and OS 37.5m (95%IC: 33.7-NA). TMPRSS2-ERG was detected in 32 pts (33%), AR gain in 11 pts and CTCs in 35 pts. No differences were observed based on TMPRSS2-ERG status for PSA response (PSA50: 81% vs 83%; p=0.8), PSA-PFS (median 12.8 vs 14.7m; HR 0.98; 95%CI 0.58-1.67; p=0.95), Rad-PFS (median 28.4 vs 26.4m; HR 1.02; 95% 0.53-1.96, p=0.95) or OS (median 36.9 vs 38.1m; HR 1.23; 95%CI 0.69-2.21, p=0.48). Plasma AR gain was associated with worse PSA-PFS (median 4.2 vs 14.7 m; p<0.0001), Rad-PFS (median 3.6 vs 28.4m; p<0.0001) and OS (median 12.7 vs 38.1m; p<0.0001). Plasma DNA and CTCs were also associated with worse outcome. Multivariate analyses of exploratory biomarkers are included in the table. Conclusions: The fusion gene TMPRSS2-ERG is not predictive nor prognostic on enzalutamide treatment in first-line chemo-naïve mCRPC patients. Plasma AR gain and CTCs are strong independent biomarkers associated with adverse outcome. Multivariate analysis of exploratory biomarkers. Clinical trial information: NCT02288936. [Table: see text]

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Krumbholz, Manuela, Abbas Agaimy, Robert Stoehr, Maximilian Burger, Sven Wach, Helge Taubert, Bernd Wullich, Arndt Hartmann, and Markus Metzler. "Molecular Composition of Genomic TMPRSS2-ERG Rearrangements in Prostate Cancer." Disease Markers 2019 (December 12, 2019): 1–8. http://dx.doi.org/10.1155/2019/5085373.

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There is increasing interest in the use of cell-free circulating tumor DNA (ctDNA) as a serum marker for therapy assessment in prostate cancer patients. Prostate cancer is characterized by relatively low numbers of mutations, and, in contrast to many other common epithelial cancers, commercially available single nucleotide mutation assays for quantification of ctDNA are insufficient for therapy assessment in this disease. However, prostate cancer shares some similarity with translocation-affected mesenchymal tumors (e.g., leukemia and Ewing sarcoma), which are common in pediatric oncology, where chromosomal translocations are used as biomarkers for quantification of the tumor burden. Approximately 50% of prostate cancers carry a chromosomal translocation resulting in generation of the TMPRSS2-ERG fusion gene, which is unique to the tumor cells of each individual patient because of variability in the fusion breakpoint sites. In the present study, we examined the structural preconditions for TMPRSS2-ERG fusion sites in comparison with mesenchymal tumors in pediatric patients to determine whether the sequence composition is suitable for the establishment of tumor-specific quantification assays in prostate cancer patients. Genomic repeat elements represent potential obstacles to establishment of quantification assays, and we found similar proportions of repeat elements at fusion sites in prostate cancer to those reported for mesenchymal tumors, where genomic fusion sequences are established as biomarkers. Our data support the development of the TMPRSS2-ERG fusion gene as a noninvasive tumor marker for therapy assessment, risk stratification, and relapse detection to improve personalized therapy strategies for patients with prostate cancer.

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Deplus, Rachel, Carine Delliaux, Nathalie Marchand, Anne Flourens, Nathalie Vanpouille, Xavier Leroy, Yvan de Launoit, and Martine Duterque-Coquillaud. "TMPRSS2-ERG fusion promotes prostate cancer metastases in bone." Oncotarget 8, no. 7 (December 31, 2016): 11827–40. http://dx.doi.org/10.18632/oncotarget.14399.

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Bismar, Tarek A., and Kiril Trpkov. "TMPRSS2-ERG gene fusion in transition zone prostate cancer." Modern Pathology 23, no. 7 (July 2010): 1040–41. http://dx.doi.org/10.1038/modpathol.2010.89.

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Fasulo, Vittorio, Massimo Lazzeri, Marinella Corbetta, Marco Paciotti, Davide Maffei, Giulia Soldà, Luigi Domanico, et al. "TMPRSS2: ERG expression in prostate cancer—Imaging and clinicopathological correlations." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 284. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.284.

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284 Background: The TMPRSS2:ERG gene fusion (T:E) is found in up to 70% of prostate cancers (PCa) and results in androgen dependent overexpression of ERG, promoting tumor growth. The early identification of T:E may be helpful even in low-risk PCa. Although T:E can be non-invasively detected in urine, its correlation with new imaging tools (MRI and high-frequency ultrasound) and clinical outcome remains vague.This study investigates T:E expression in patients scheduled for random/software-assisted MRI or micro-ultrasound (29Mhz) fusion biopsy. Methods: This is a prospective cohort study in patients with suspected PCa enrolled between 2016 and 2019, approved by local authorities with Prot. N. 336/19, 14/05/2019. Patients underwent systematic US-guided biopsy, plus targeted biopsy if they had ³1 suspicious lesion (PI-RADS V.2 >2) at mpMRI or PRIMUS >2 at MICRO-US. For each patient, 1 prostatic core from the highest PI-RADS or PRIMUS lesion was collected for T:E analysis (a core from the right lobe in negative patients). Histological analyses were performed by experienced genitourinary pathologists. RNA was extracted from a dedicated fresh biopsy and RT-PCR was performed with different primer couples to detect the most frequent T:E fusions. All amplified products were checked by sequencing. Results: The cohort consists of 92 patients (median PSA 7.13 ng/ml, IQR 5.25-11.04 - average age 65ys), 81 with a diagnosis of PCa after biopsy. mpMRI was performed on 63 (68.5%) patients and was positive in 58 (92%), who underwent fusion biopsy. T:E fusion transcripts were detected in 23.5% of individuals with a diagnosis of PCa. Among patients positive for T:E, those analyzed by MRI were 100% positive (73% PI-RADS ≥4), those analyzed by MICRO-US were 83% positive. Sensitivity of the T:E assay for any PCa was 23.5%, specificity 100%, with negative and positive predicting values of 15% and 100%. There was no correlation between T:E and family history, PSA, PIRADS, PRI-MUS and Gleason score. Conclusions: Our finding showed a 100% of specificity making T:E an attractive tool for early cancer detection. In the future, identification of T:E in semen could represent a screening test for clinical stratification of patients with suspected PCa.

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Mwamukonda, K., Y. Chen, L. Ravindranath, B. Furusato, Y. Hu, J. Sterbis, D. Osborn, et al. "Quantitative expression of TMPRSS2 transcript in prostate tumor cells reflects TMPRSS2–ERG fusion status." Prostate Cancer and Prostatic Diseases 13, no. 1 (July 14, 2009): 47–51. http://dx.doi.org/10.1038/pcan.2009.28.

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Kim, Jung-Sun, Justin M. Roberts, William E. Bingman, Longjiang Shao, Jianghua Wang, Michael M. Ittmann, and Nancy L. Weigel. "The Prostate Cancer TMPRSS2:ERG Fusion Synergizes With the Vitamin D Receptor (VDR) to Induce CYP24A1 Expression-Limiting VDR Signaling." Endocrinology 155, no. 9 (September 1, 2014): 3262–73. http://dx.doi.org/10.1210/en.2013-2019.

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Abstract A number of preclinical studies have shown that the activation of the vitamin D receptor (VDR) reduces prostate cancer (PCa) cell and tumor growth. The majority of human PCas express a transmembrane protease serine 2 (TMPRSS2):erythroblast transformation-specific (ETS) fusion gene, but most preclinical studies have been performed in PCa models lacking TMPRSS2:ETS in part due to the limited availability of model systems expressing endogenous TMPRSS2:ETS. The level of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D), is controlled in part by VDR-dependent induction of cytochrome P450, family 24, subfamily 1, polypeptide1 (CYP24A1), which metabolizes 1,25D to an inactive form. Because ETS factors can cooperate with VDR to induce rat CYP24A1, we tested whether TMPRSS2:ETS would cause aberrant induction of human CYP24A1 limiting the activity of VDR. In TMPRSS2:ETS positive VCaP cells, depletion of TMPRSS2:ETS substantially reduced 1,25D-mediated CYP24A1 induction. Artificial expression of the type VI+72 TMPRSS2:ETS isoform in LNCaP cells synergized with 1,25D to greatly increase CYP24A1 expression. Thus, one of the early effects of TMPRSS2:ETS in prostate cells is likely a reduction in intracellular 1,25D, which may lead to increased proliferation. Next, we tested the net effect of VDR action in TMPRSS2:ETS containing PCa tumors in vivo. Unlike previous animal studies performed on PCa tumors lacking TMPRSS2:ETS, EB1089 (seocalcitol) (a less calcemic analog of 1,25D) did not inhibit the growth of TMPRSS2:ETS containing VCaP tumors in vivo, suggesting that the presence of TMPRSS2:ETS may limit the growth inhibitory actions of VDR. Our findings suggest that patients with TMPRSS2:ETS negative tumors may be more responsive to VDR-mediated growth inhibition and that TMPRSS2:ETS status should be considered in future clinical trials.

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Wang, Zhu, Yuliang Wang, Jianwen Zhang, Qiyi Hu, Fan Zhi, Shengping Zhang, Dengqi Mao, Ying Zhang, and Hui Liang. "Significance of the TMPRSS2:ERG gene fusion in prostate cancer." Molecular Medicine Reports 16, no. 4 (August 18, 2017): 5450–58. http://dx.doi.org/10.3892/mmr.2017.7281.

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Tomlins, Scott A., Bharathi Laxman, Sooryanarayana Varambally, Xuhong Cao, Jindan Yu, Beth E. Helgeson, Qi Cao, et al. "Role of the TMPRSS2-ERG Gene Fusion in Prostate Cancer." Neoplasia 10, no. 2 (February 2008): 177—IN9. http://dx.doi.org/10.1593/neo.07822.

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Brooks, James. "Role of the TMPRSS2-ERG gene fusion in prostate cancer." Urologic Oncology: Seminars and Original Investigations 26, no. 5 (September 2008): 569. http://dx.doi.org/10.1016/j.urolonc.2008.07.011.

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Cheng, Liang, Darrell D. Davidson, Gregory T. MacLennan, Antonio Lopez-Beltran, Rodolfo Montironi, Mingsheng Wang, Puay-Hoon Tan, Lee Ann Baldridge, and Shaobo Zhang. "Atypical Adenomatous Hyperplasia of Prostate Lacks TMPRSS2-ERG Gene Fusion." American Journal of Surgical Pathology 37, no. 10 (October 2013): 1550–54. http://dx.doi.org/10.1097/pas.0b013e318294e9bc.

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Albadine, Roula, Mathieu Latour, Antoun Toubaji, Michael Haffner, William B. Isaacs, Elizabeth A Platz, Alan K. Meeker, Angelo M. Demarzo, Jonathan I. Epstein, and George J. Netto. "TMPRSS2–ERG gene fusion status in minute (minimal) prostatic adenocarcinoma." Modern Pathology 22, no. 11 (September 4, 2009): 1415–22. http://dx.doi.org/10.1038/modpathol.2009.121.

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Stone, Louise. "Stuck in the middle: interstitial genes in TMPRSS2–ERG fusion." Nature Reviews Urology 15, no. 1 (December 5, 2017): 3. http://dx.doi.org/10.1038/nrurol.2017.208.

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Clark, J., S. Merson, S. Jhavar, P. Flohr, S. Edwards, C. S. Foster, R. Eeles, et al. "Diversity of TMPRSS2-ERG fusion transcripts in the human prostate." Oncogene 26, no. 18 (October 16, 2006): 2667–73. http://dx.doi.org/10.1038/sj.onc.1210070.

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Bastus, Nuria Coll, Lara K. Boyd, Xueying Mao, Elzbieta Stankiewicz, Sakunthala C. Kudahetti, R. Tim D. Oliver, Daniel M. Berney, and Yong-Jie Lu. "Androgen-Induced TMPRSS2:ERG Fusion in Nonmalignant Prostate Epithelial Cells." Cancer Research 70, no. 23 (October 14, 2010): 9544–48. http://dx.doi.org/10.1158/0008-5472.can-10-1638.

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Adra, Nabil, Liang Cheng, Nasser H. Hanna, and Greg Durm. "TMPRSS2-ERG Fusion in an Uncommon Presentation of Prostate Cancer." Clinical Genitourinary Cancer 15, no. 3 (June 2017): e489-e491. http://dx.doi.org/10.1016/j.clgc.2017.01.020.

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Velaeti, S., E. Dimitriadis, K. Kontogianni-Katsarou, A. Savvani, E. Sdrolia, G. Pantazi, S. Stefanakis, T. Trangas, N. Pandis, and K. Petraki. "Detection of TMPRSS2-ERG fusion gene in benign prostatic hyperplasia." Tumor Biology 35, no. 10 (June 25, 2014): 9597–602. http://dx.doi.org/10.1007/s13277-014-2250-0.

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Mucci, Lorelei A., Thomas Ahearn, Kathryn Penney, Andreas Pettersson, Rebecca E. Graff, Philip W. Kantoff, Stephen Finn, and Massimo Loda. "Precision prevention of TMPRSS2:ERG prostate cancer." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 78. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.78.

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78 Background: Increased integration of tumor biomarker data into prostate cancer epidemiology studies is needed to identify molecular subtypes that underlie its etiology and progression. We hypothesize that the TMPRSS2:ERG gene fusion is a unique prostate cancer subtype that is etiologically distinct from cancers lacking TMPRSS2:ERG. Methods: We leveraged the Physicians’ Health Study and Health Professionals Follow-up Study cohort data on pre- and post-diagnostic lifestyle factors, inherited genetic variants, circulating biomarkers, and clinical data and follow-up for 30 years. We have a tumor repository of men with prostate cancer and tumor tissue microarrays. Using immunohistochemistry, we characterized TMPRSS2:ERG status for 1,491 incident prostate cancer cases in these cohorts, and also have biomarker data on a range of additional markers from immunohistochemistry and mRNA expression profiling. Results: Fifty percent of prostate cancer cases were ERG-positive. ERG-positive cancers show much higher expression of insulin/IGF signaling, PTEN loss, higher VDR expression, as well as expression of mismatch repair genes. In contrast, ERG-negative prostate cancer is characterized by increased presence of chronic inflammation and atrophy. We found higher pre-diagnostic free testosterone levels, but not other sex hormones, were associated with increased risk of ERG-positive (OR = 1.4, 95% CI = 1.0-1.8) but not ERG-negative disease (OR = 0.9, 95% CI = 0.7-1.2). Of 39 known genetic risk loci, six were significantly associated (p < 0.05) with ERG+ versus ERG- cancer (2 expected by chance). Prostate cancer risk factors such as taller height (an indicator of growth factors in puberty) are uniquely associated with ERG-positive prostate cancer. Moreover, we observe a complex interaction of components of insulin/IGF and ERG-status on prostate cancer mortality. Conclusions: TMPRSS2:ERG is a highly prevalent somatic event in prostate cancer that likely defines a unique molecular subtype of this common disease. Understanding the differences between these two prostate cancer subtypes may enhance opportunities for prevention.

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Wang, Shiyuan, Qi Zhang, Dandan Xu, Yi Pan, Yingli Lv, Xiaowen Chen, Yongchun Zuo, and Lei Yang. "Characterize the difference between TMPRSS2-ERG and non-TMPRSS2-ERG fusion patients by clinical and biological characteristics in prostate cancer." Gene 679 (December 2018): 186–94. http://dx.doi.org/10.1016/j.gene.2018.09.006.

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SABALIAUSKAITĖ, Rasa, Donatas PETROŠKA, Darius DASEVIČIUS, Arvydas LAURINAVIČIUS, Feliksas JANKEVIČIUS, Juozas R. LAZUTKA, and Sonata JARMALAITĖ. "Molecular analysis of multifocal prostate cancer cases." Acta medica Lituanica 18, no. 4 (October 1, 2011): 147–55. http://dx.doi.org/10.6001/actamedica.v18i4.1867.

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Background. Prostate cancer (PCa) is usually a multifocal disease with different foci displaying histological and molecular heterogeneity. Biopsy-based pathology diagnosis of PCa may not be representative of the entire tumour; thus, markers more precisely characterizing every focus of multifocal PCa are highly instrumental for a better testing of PCa. Materials and Methods. Two distant foci of prostate adenocarcinoma were obtained from prostatectomy specimens of ten patients with pT2–pT3 stage PCa. The expression of TMPRSS2 : ERG, TMPRSS2 : ETV1, and TERT was assessed by means of reverse transcription PCR and quantified using the real-time-based approach. Ki-67, ERG, EMA, AMACR, p16, and p53 expression was evaluated by means of immunohistochemistry (IHC) on tissue microarrays (TMA). Results. Two out of ten cases were identified with different Gleason scores in paired foci of PCa. The expression of most of the IHC markers was quite even between TMA cores of each PCa case, with p16 showing the highest level of heterogeneity (44%; 4/9); 80% (8/10) of multifocal PCa expressed different variants of the TMPRSS2 : ERG transcript or showed a varying status of fusion positivity in paired foci, and the expression levels of the transcript were also heterogeneous. Similarly, 90% (9/10) of PCa showed a different positivity for TERT expression in paired foci. Conclusions. Measurement of TMPRSS2 : ERG and TERT expression offers a valuable tool for identifying most aggressive tumour foci and selecting a relevant treatment of PCa. Keywords: prostate cancer, multifocality, TMPRSS2 : ERG, telomerase

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Gupta, Sachin Kumar, Liming Luo, and Laising Yen. "RNA-mediated gene fusion in mammalian cells." Proceedings of the National Academy of Sciences 115, no. 52 (December 11, 2018): E12295—E12304. http://dx.doi.org/10.1073/pnas.1814704115.

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One of the hallmarks of cancer is the formation of oncogenic fusion genes as a result of chromosomal translocations. Fusion genes are presumed to form before fusion RNA expression. However, studies have reported the presence of fusion RNAs in individuals who were negative for chromosomal translocations. These observations give rise to “the cart before the horse” hypothesis, in which the genesis of a fusion RNA precedes the fusion gene. The fusion RNA then guides the genomic rearrangements that ultimately result in a gene fusion. However, RNA-mediated genomic rearrangements in mammalian cells have never been demonstrated. Here we provide evidence that expression of a chimeric RNA drives formation of a specified gene fusion via genomic rearrangement in mammalian cells. The process is: (i) specified by the sequence of chimeric RNA involved, (ii) facilitated by physiological hormone levels, (iii) permissible regardless of intrachromosomal (TMPRSS2–ERG) or interchromosomal (TMPRSS2–ETV1) fusion, and (iv) can occur in normal cells before malignant transformation. We demonstrate that, contrary to “the cart before the horse” model, it is the antisense rather than sense chimeric RNAs that effectively drive gene fusion, and that this disparity can be explained by transcriptional conflict. Furthermore, we identified an endogenous RNA AZI1 that functions as the “initiator” RNA to induce TMPRSS2–ERG fusion. RNA-driven gene fusion demonstrated in this report provides important insight in early disease mechanisms, and could have fundamental implications in the biology of mammalian genome stability, as well as gene-editing technology via mechanisms native to mammalian cells.

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Schmidt, Folke, Kirsten Mertz, Sven Perner, Scott A. Tomlins, Joachim W. Thuroff, Arul M. Chinnaiyan, and Mark A. Rubin. "ERG EXPRESSION VARIES IN DIFFERENT ISOFORMS OF TMPRSS2:ERG GENE FUSION IN PROSTATE CANCER." Journal of Urology 179, no. 4S (April 2008): 393. http://dx.doi.org/10.1016/s0022-5347(08)61150-7.

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Niraula, S., U. Emmeneger, L. Adams, I. Tannock, S. S. Sridhar, J. J. Knox, J. R. Day, J. Manthe, J. Groskopf, and A. M. Joshua. "Use of serum and tissue biomarker analysis embedded in a phase II clinical trial of cytarabine in castration-refractory prostate cancer to investigate prostate cancer biology." Journal of Clinical Oncology 29, no. 7_suppl (March 1, 2011): 59. http://dx.doi.org/10.1200/jco.2011.29.7_suppl.59.

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59 Background: Other than the androgen receptor, the TMPRSS2-ERG genomic aberrations in prostate cancer provide the first recent opportunity to target therapy in castration refractory prostate cancer (CRPC). We initiated a phase II clinical trial of cytarabine in docetaxel refractory CRPC on the basis of microarray, in vitro and case report evidence that cytarabine may be particularly effective in men harbouring abnormalities of the ERG oncogenes. Embedded in this clinical trial was the first use of blood mRNA levels of prostate cancer related genes as biomarkers of response and prognosis. Methods: Patients with docetaxel refractory progressive CRPC received intravenous cytarabine at doses between 1g/m2-0.25 g/m2 q3 weekly. Responses were defined according to PCWG2C. 10 patients were enrolled between June 2007 and January 2010. TMPRSS2:ERG, PSA and PCA3 mRNA copies in whole blood collected with PAXgene tubes at the beginning of each cycle and at trial termination were quantified using transcription-mediated amplification assays. The prototype TMPRSS2:ERG assay detects the gene fusion isoform TMPRSS2 exon1 to ERG exon4. Results: No patients demonstrated a serum PSA response (PCWG2C). The average number of cycles administered was 2.6. Significant toxicities including grade 3-4 thrombocytopenia (2) and grade 3-4 neutropenia (3). These toxicities necessitated several dose reductions in the protocol, however most patients were removed from trial for serum PSA progression alone. PCA3 and PSA mRNAs were detectable in 8/10 and 9/10 cases, respectively; there was no correlation between serum PSA and PCA3 or PSA mRNA copy levels in blood. Testing for TMPRSS2:ERG in blood was able to predict the presence or absence of the TMPRSS2-ERG rearrangement in 9/10 cases when compared to 3 colour FISH carried out on baseline biopsies/ prostatectomies (2/10 positive for Exon 4:Exon 1 deletion). Conclusions: Cytarabine administation is ineffective in docetaxel refractory CRPC. Blood mRNA levels of prostate cancer genes reveal novel aspects of prostate cancer biology and have implications for the understanding of circulating tumour cells. [Table: see text]

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Soller, W., M. Johansson Soller, M. Isaksson, P. Elfving, P. A. Abrahamsson, R. Lundgren, and I. Panagopoulos. "HIGH FREQUENCY OF THE TMPRSS2/ERG FUSION GENE IN PROSTATE CANCER." European Urology Supplements 5, no. 14 (September 2006): 789. http://dx.doi.org/10.1016/s1569-9056(06)61261-x.

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Kalogeropoulos, T., S. Velaeti, E. Dimitriadis, T. Arvanitakis, K. Kontogianni-Katsarou, A. Savvani, A. Apostolaki, et al. "355 DETECTION OF TMPRSS2-ERG FUSION GENES IN PROSTATE BENIGN HYPERPLASIA." European Urology Supplements 8, no. 4 (March 2009): 209. http://dx.doi.org/10.1016/s1569-9056(09)60358-4.

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Salagierski, Maciej, and Jack A. Schalken. "Molecular Diagnosis of Prostate Cancer: PCA3 and TMPRSS2:ERG Gene Fusion." Journal of Urology 187, no. 3 (March 2012): 795–801. http://dx.doi.org/10.1016/j.juro.2011.10.133.

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Velaeti, S., T. Kalogeropoulos, T. Karaolidis, E. Dimitriadis, K. Kontogianni-Katsarou, A. Savvani, S. Mpisias, S. Stefanakis, N. Pandis, and K. Petraki. "S21 Detection of TMPRSS2-ERG fusion gene in benign prostate hyperplasia." European Urology Supplements 8, no. 8 (September 2009): 614. http://dx.doi.org/10.1016/s1569-9056(09)74902-4.

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Gao, Chunling, Bungo Furusato, David G. McLeod, Shiv Srivastava, Gyorgy Petrovics, and Isabell A. Sesterhenn. "1125: Mapping of TMPRSS2-ERG Fusion in Multi-Focal Prostate Cancer." Journal of Urology 177, no. 4S (April 2007): 371–72. http://dx.doi.org/10.1016/s0022-5347(18)31339-9.

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Mao, Xueying, Greg Shaw, Sharon Y. James, Patricia Purkis, Sakunthala C. Kudahetti, Theodora Tsigani, Saname Kia, et al. "Detection of TMPRSS2:ERG fusion gene in circulating prostate cancer cells." Asian Journal of Andrology 10, no. 3 (May 2008): 467–73. http://dx.doi.org/10.1111/j.1745-7262.2008.00401.x.

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Journal articles on the topic 'Fusion TMPRSS2:ERG'

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