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The data on tumor molecular profiling of European patients with prostate cancer is limited. Our aim was to evaluate the prevalence and prognostic and predictive values of gene alterations in unselected patients with prostate cancer. The presence of gene alterations was assessed in patients with histologically confirmed prostate cancer using the ForeSENTIA® Prostate panel (Medicover Genetics), targeting 36 clinically relevant genes and microsatellite instability testing. The primary endpoint was the prevalence of gene alterations in homologous recombination repair (HRR) genes. Overall, 196 patients with prostate cancer were evaluated (median age 72.2 years, metastatic disease in 141 (71.9%) patients). Gene alterations were identified in 120 (61%) patients, while alteration in HRR genes were identified in 34 (17.3%) patients. The most commonly mutated HRR genes were ATM (17, 8.7%), BRCA2 (9, 4.6%) and BRCA1 (4, 2%). The presence of HRR gene alterations was not associated with advanced stage (p = 0.21), age at diagnosis (p = 0.28), Gleason score (p = 0.17) or overall survival (HR 0.72; 95% CI: 0.41–1.26; p = 0.251). We identified clinically relevant somatic gene alterations in European patients with prostate cancer. These molecular alterations have prognostic significance and therapeutic implications and/or may trigger genetic testing in selected patients. In the era of precision medicine, prospective research on the predictive role of these alterations for innovative treatments or their combinations is warranted. [ABSTRACT FROM AUTHOR]

Molecular heterogeneity in prostate cancer (PCa) is one of the key reasons underlying the differing likelihoods of recurrence after surgical treatment in individual patients of the same clinical category. In this study, we performed RNA-Seq profiling of 58 localized PCa and 43 locally advanced PCa tissue samples obtained as a result of radical prostatectomy on a cohort of Russian patients. Based on bioinformatics analysis, we examined features of the transcriptome profiles within the high-risk group, including within the most commonly represented molecular subtype, TMPRSS2-ERG. The most significantly affected biological processes in the samples were also identified, so that they may be further studied in the search for new potential therapeutic targets for the categories of PCa under consideration. The highest predictive potential was found with the EEF1A1P5, RPLP0P6, ZNF483, CIBAR1, HECTD2, OGN, and CLIC4 genes. We also reviewed the main transcriptome changes in the groups at intermediate risk of PCa—Gleason Score 7 (groups 2 and 3 according to the ISUP classification)—on the basis of which the LPL, MYC, and TWIST1 genes were identified as promising additional prognostic markers, the statistical significance of which was confirmed using qPCR validation. [ABSTRACT FROM AUTHOR]

Abstract Purpose Specific gene fusions and their fusion products (chimeric RNA and protein) have served as ideal diagnostic markers and therapeutic targets for cancer. However, few systematic studies for chimeric RNAs have been conducted in neuroendocrine prostate cancer (NEPC). In this study, we explored the landscape of chimeric RNAs in different types of prostate cancer (PCa) cell lines and aimed to identify chimeric RNAs specifically expressed in NEPC. Methods To do so, we employed the RNA-seq data of eight prostate related cell lines from Cancer Cell Line Encyclopedia (CCLE) for chimeric RNA identification. Multiple filtering criteria were used and the candidate chimeric RNAs were characterized at multiple levels and from various angles. We then performed experimental validation on all 80 candidates, and focused on the ones that are specific to NEPC. Lastly, we studied the clinical relevance and effect of one chimera in neuroendocrine process. Results Out of 80 candidates, 15 were confirmed to be expressed preferentially in NEPC lines. Among them, 13 of the 15 were found to be specifically expressed in NEPC, and four were further validated in another NEPC cell line. Importantly, in silico analysis showed that tumor malignancy may be correlated to the level of these chimeric RNAs. Clinically, the expression of TMPRSS2-ERG (e2e4) was elevated in tumor tissues and indicated poor clinical prognosis, whereas the parental wild type transcripts had no such association. Furthermore, compared to the most frequently detected TMPRSS2-ERG form (e1e4), e2e4 encodes 31 more amino acids and accelerated neuroendocrine process of prostate cancer. Conclusions In summary, these findings painted the landscape of chimeric RNA in NEPC and supported the idea that some chimeric RNAs may represent additional biomarkers and/or treatment targets independent of parental gene transcripts.

Prostate cancer (PCa) is one of cancer with of the highest incidence and mortality worldwide. Current disease prognostic markers do not differentiate aggressive from indolent PCa with sufficient certainty, and characterization by molecular subtypes has been sought to allow a better classification. TMPRSS2‐ERG, SPOP, FOXA1, and IDH1 molecular subtypes have been described, but the association of these subtypes with prognosis in PCa is unclear; their frequency in Colombian patients is also unknown. Formalin‐fixed and paraffin‐embedded samples of radical prostatectomy from 112 patients with PCa were used. The TMPRSS2‐ERG subtype was assessed with fluorescent in situ hybridization. The mutations in SPOP, FOXA1, and IDH1 in hot‐spot regions were evaluated using Sanger sequencing. Fusion was detected in 71 patients (63.4%). No statistically significant differences were found between the state of fusion and the variables analyzed. In the 41 fusion‐negative cases (36.6%), two patients (4.9%) had missense mutations in SPOP (p.F102C and p.F133L), representing a 1.8% of the overall cohort. The low frequency of this subtype in Colombians could be explained by the reported variability in the frequency of these mutations according to the population (5%–20%). No mutations were found in FOXA1 in the cases analyzed. The synonym SNP rs11554137 IDH1105GGT was found in tumor tissue but not in the normal tissue in one case. A larger cohort of Colombian PCa patients is needed for future studies to validate these findings and gain a better understanding of the molecular profile of this cancer in our population and if there are any differences by Colombian regions. [ABSTRACT FROM AUTHOR]

Transformation to squamous cell carcinoma (SCC) after initial treatment of a primary prostate adenocarcinoma is rare and typically results in rapid treatment-refractory disease progression and death. Here, we present a case of a 70-year-old man who was initially treated with prostatectomy and radiotherapy, and later developed bone metastases. After commencing systemic therapy with androgen deprivation therapy (ADT) and apalutamide, his prostate-specific antigen (PSA) declined to undetectable levels, yet short-interval imaging demonstrated oligo-progression at T4, with biopsy specimen demonstrating pure SCC. Molecular profiling of both the primary prostate tumor and T4 demonstrated alterations in TMPRSS2-ERG, TP53, and FOXA1 confirming site of origin, with loss of RNF43 in the squamous metastasis. He was treated with stereotactic body radiation therapy to the SCC metastasis and continued on ADT and apalutamide with stable disease for a year post-radiation. This case highlights the importance of imaging to detect non– PSA-producing metastatic disease, the utility of radiation therapy in oligo-progression, and use of molecular profiling to provide insights into the pathogenesis of histologic transformation.

Prostate cancer is a highly heterogeneous disease, understanding the crosstalk between complex genomic and epigenomic alterations will aid in developing targeted therapeutics. We demonstrate that, even though snail family transcriptional repressor 2 (SNAI2) is frequently amplified in prostate cancer, it is epigenetically silenced in this disease, with dynamic changes in SNAI2 levels showing distinct clinical relevance. Integrative clinical data from 18 prostate cancer cohorts and experimental evidence showed that gene fusion between transmembrane serine protease 2 (TMPRSS2) and ETS transcription factor ERG (ERG) (TMPRSS2–ERG fusion) is involved in the silencing of SNAI2. We created a silencer score to evaluate epigenetic repression of SNAI2, which can be reversed by treatment with DNA methyltransferase inhibitors and histone deacetylase inhibitors. Silencing of SNAI2 facilitated tumor cell proliferation and luminal differentiation. Furthermore, SNAI2 has a major influence on the tumor microenvironment by reactivating tumor stroma and creating an immunosuppressive microenvironment in prostate cancer. Importantly, SNAI2 expression levels in part determine sensitivity to the cancer drugs dasatinib and panobinostat. For the first time, we defined the distinct clinical relevance of SNAI2 expression at different disease stages. We elucidated how epigenetic silencing of SNAI2 controls the dynamic changes of SNAI2 expression that are essential for tumor initiation and progression and discovered that restoring SNAI2 expression by treatment with panobinostat enhances dasatinib sensitivity, indicating a new therapeutic strategy for prostate cancer.

Following radical surgery, patients may suffer a relapse. It is important to identify such patients so that therapy tactics can be modified appropriately. Existing stratification schemes do not display the probability of recurrence with enough precision since locally advanced prostate cancer (PCa) is classified as high-risk but is not ranked in greater detail. Between 40 and 50% of PCa cases belong to the TMPRSS2-ERG subtype that is a sufficiently homogeneous group for high-precision prognostic marker search to be possible. This study includes two independent cohorts and is based on high throughput sequencing and qPCR data. As a result, we have been able to suggest a perspective-trained model involving a deep neural network based on both qPCR data for mRNA and miRNA and clinicopathological criteria that can be used for recurrence risk forecasts in patients with TMPRSS2-ERG-positive, locally advanced PCa (the model uses ALDH3A2 + ODF2 + QSOX2 + hsa-miR-503-5p + ISUP + pT, with an AUC = 0.944). In addition to the prognostic model's use of identified differentially expressed genes and miRNAs, miRNA–target pairs were found that correlate with the prognosis and can be presented as an interactome network. [ABSTRACT FROM AUTHOR]

Purpose: Specific gene fusions and their fusion products (chimeric RNA and protein) have served as ideal diagnostic markers and therapeutic targets for cancer. However, few systematic studies for chimeric RNAs have been conducted in neuroendocrine prostate cancer (NEPC). In this study, we explored the landscape of chimeric RNAs in different types of prostate cancer (PCa) cell lines and aimed to identify chimeric RNAs specifically expressed in NEPC. Methods: To do so, we employed the RNA-seq data of eight prostate related cell lines from Cancer Cell Line Encyclopedia (CCLE) for chimeric RNA identification. Multiple filtering criteria were used and the candidate chimeric RNAs were characterized at multiple levels and from various angles. We then performed experimental validation on all 80 candidates, and focused on the ones that are specific to NEPC. Lastly, we studied the clinical relevance and effect of one chimera in neuroendocrine process. Results: Out of 80 candidates, 15 were confirmed to be expressed preferentially in NEPC lines. Among them, 13 of the 15 were found to be specifically expressed in NEPC, and four were further validated in another NEPC cell line. Importantly, in silico analysis showed that tumor malignancy may be correlated to the level of these chimeric RNAs. Clinically, the expression of TMPRSS2-ERG (e2e4) was elevated in tumor tissues and indicated poor clinical prognosis, whereas the parental wild type transcripts had no such association. Furthermore, compared to the most frequently detected TMPRSS2-ERG form (e1e4), e2e4 encodes 31 more amino acids and accelerated neuroendocrine process of prostate cancer. Conclusions: In summary, these findings painted the landscape of chimeric RNA in NEPC and supported the idea that some chimeric RNAs may represent additional biomarkers and/or treatment targets independent of parental gene transcripts. [ABSTRACT FROM AUTHOR]

One common genetic alteration in cancer is gene fusion resulting from chromosomal translocations. The mechanisms that create such oncogenic fusion genes are not well understood. Previously, we provided the direct evidence that expression of a designed chimeric RNA can drive the formation of TMPRSS2-ERG gene fusion. Central to this RNA-mediated gene fusion mechanism is a proposed three-way junction formed by RNA/DNA hybrid and the intergenic DNA stem formed by target genes. In this study, we determined the important parameters for chimeric RNA-mediated gene fusion using TMPRSS2-ERG fusion gene as the model. Our results indicate that both the chimeric RNA lengths and the sizes of unpaired bulges play important roles in inducing TMPRSS2-ERG gene fusion. The optimal length of unpaired bulges was about 35 nt, while the optimal chimeric RNA length was about 50 nt for targeting. These observations were consistent regardless of the target locations within TMPRSS2 and ERG genes. These empirically determined parameters provide important insight for searching cellular RNAs that may initiate oncogenic fusion genes. The knowledge could also facilitate the development of useful genomic technology for manipulating mammalian genomes. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is one of the most common and socially significant oncological diseases among men. Bioinformatic analysis of omics data allows identifying molecular genetic changes associated with the disease development, as well as markers of prognosis and response to therapy. Alterations in DNA methylation and histone modification profiles widely occur in malignant tumors. In this study, we analyzed changes in DNA methylation in three groups of PC patients based on data from The Cancer Genome Atlas project (TCGA, https://portal.gdc.cancer.gov): (1) high- and intermediate-risk of the tumor progression, (2) favorable and unfavorable prognoses within the high-risk group, and (3) TMPRSS2-ERG-positive (tumors with TMPRSS2-ERG fusion transcript) and TMPRSS2-ERG-free cases within the high-risk group. We found eight CpG sites (cg07548607, cg13533340, cg16643088, cg18467168, cg23324953, cg23753247, cg25773620, and cg27148952) hypermethylated in the high-risk group compared with the intermediate-risk group of PC. Seven differentially methylated CpG sites (cg00063748, cg06834698, cg18607127, cg25273707, cg01704198, cg02067712, and cg02157224) were associated with unfavorable prognosis within the high-risk group. Six CpG sites (cg01138171, cg14060519, cg19570244, cg24492886, cg25605277, and cg26228280) were hypomethylated in TMPRSS2-ERG-positive PC compared to TMPRSS2-ERG-negative tumors within the high-risk group. The CpG sites were localized, predominantly, in regulatory genome regions belonging to promoters of the following genes: ARHGEF4, C6orf141, C8orf86, CLASP2, CSRNP1, GDA, GSX1, IQSEC1, MYOF, OR10A3, PLCD1, PLEC1, PRDM16, PTAFR, RP11-844P9.2, SCYL3, VPS13D, WT1, and ZSWIM2. For these genes, analysis of differential expression and its correlation with CpG site methylation (β-value level) was also performed. In addition, STK33 and PLCD1 had similar changes in colorectal cancer. As for the CSRNP1, the ARHGEF4, and the WT1 genes, misregulated expression levels were mentioned in lung, liver, pancreatic and androgen-independent prostate cancer. The potential impact of changed methylation on the mRNA level was determined for the CSRNP1, STK33, PLCD1, ARHGEF4, WT1, SCYL3, and VPS13D genes. The above CpG sites could be considered as potential prognostic markers of the high-risk group of PC.

Abstract Background Prostate cancer (PCa) is the second cause of cancer related death in North American men. Androgens play an important role in its progression by regulating the expression of several genes including fusion ones that results from structural chromosome rearrangements. TMPRSS2-ERG is a fusion gene commonly observed in over 50% of PCa tumors, and its expression can be transcriptionally regulated by the androgen receptor (AR) given its androgen responsive elements. TMPRSS2-ERG could be involved in epithelial–mesenchymal transition (EMT) during tumor development. ERG has been reported as a key transcriptional factor in the AR-ERG-WNT network where five SFRP proteins, structurally similar to WNT ligands and considered to be WNT pathway antagonists, can regulate signaling in the extracellular space by binding to WNT proteins or Frizzled receptors. It has been shown that over-expression of SFRP1 protein can regulate the transcriptional activity of AR and inhibits the formation of colonies in LNCaP cells. However, the effect of SFRP1 has been controversial since differential effects have been observed depending on its concentration and tissue location. In this study, we explored the role of exogenous SFRP1 protein in cells expressing the TMPRSS2-ERG fusion. Methods To evaluate the effect of exogenous SFRP1 protein on PCa cells expressing TMPRSS2-ERG, we performed in silico analysis from TCGA cohort, expression assays by RT-qPCR and Western blot, cell viability and cell cycle measurements by cytometry, migration and invasion assays by xCELLigance system and murine xenografts. Results We demonstrated that SFRP1 protein increased ERG expression by promoting cellular migration in vitro and increasing tumor growth in vivo in PCa cells with the TMPRSS2-ERG fusion. Conclusions These results suggest the possible role of exogenous SFRP1 protein as a modulator of AR-ERG-WNT signaling network in cells positive to TMPRSS2-ERG. Further, investigation is needed to determine if SFRP1 protein could be a target in against this type of PCa.

Abstract Background Prostate cancer (PC) can display very heterogeneous phenotypes ranging from indolent asymptomatic to aggressive lethal forms. Understanding how these PC subtypes vary in their striving for energy and anabolic molecules is of fundamental importance for developing more effective therapies and diagnostics. Here, we carried out an extensive analysis of prostate tissue samples to reveal metabolic alterations during PC development and disease progression and furthermore between TMPRSS2-ERG rearrangement-positive and -negative PC subclasses. Methods Comprehensive metabolomics analysis of prostate tissue samples was performed by non-destructive high-resolution magic angle spinning nuclear magnetic resonance (1H HR MAS NMR). Subsequently, samples underwent moderate extraction, leaving tissue morphology intact for histopathological characterization. Metabolites in tissue extracts were identified by 1H/31P NMR and liquid chromatography-mass spectrometry (LC-MS). These metabolomics profiles were analyzed by chemometric tools and the outcome was further validated using proteomic data from a separate sample cohort. Results The obtained metabolite patterns significantly differed between PC and benign tissue and between samples with high and low Gleason score (GS). Five key metabolites (phosphocholine, glutamate, hypoxanthine, arginine and α-glucose) were identified, who were sufficient to differentiate between cancer and benign tissue and between high to low GS. In ERG-positive PC, the analysis revealed several acylcarnitines among the increased metabolites together with decreased levels of proteins involved in β-oxidation; indicating decreased acyl-CoAs oxidation in ERG-positive tumors. The ERG-positive group also showed increased levels of metabolites and proteins involved in purine catabolism; a potential sign of increased DNA damage and oxidative stress. Conclusions Our comprehensive metabolomic analysis strongly indicates that ERG-positive PC and ERG-negative PC should be considered as different subtypes of PC; a fact requiring different, sub-type specific treatment strategies for affected patients.

Fusion between the transmembrane protease serine 2 and v-ets erythroblastosis virus E26 oncogene homolog (TMPRSS2-ERG fusion) is a common genetic alteration in prostate cancer among Western populations and has been suggested as playing a role in tumorigenesis and progression of prostate cancer. However, the prevalence of TMPRSS2-ERG fusion differs among different ethnic groups, and contradictory results have been reported in Asian patients. We aim to evaluate the prevalence and significance of TMPRSS2-ERG fusion as a molecular subtyping and prognosis indicator of prostate cancer in Asians. We identified the fusion status in 669 samples from prostate biopsy and radical prostatectomy by fluorescence in situ hybridization and/or immunohistochemistry in China. We examined the association of TMPRSS2-ERG fusion with clinicopathological characteristics and biochemical recurrence by Chi-square test and Kaplan–Meier analysis. Finally, a systematic review was performed to investigate the positive rate of the fusion in Asian prostate cancer patients. McNemar's test was employed to compare the positive rates of TMPRSS2-ERG fusion detected using different methods. The positive rates of TMPRSS2-ERG fusion were 16% in our samples and 27% in Asian patients. In our samples, 9.4% and 19.3% of cases were recognized as fusion positive by fluorescence in situ hybridization and immunohistochemistry, respectively. No significant association between the fusion and clinical parameters was observed. TMPRSS2-ERG fusion is not a frequent genomic alteration among Asian prostate cancer patients and has limited significance in clinical practices in China. Besides ethnic difference, detection methods potentially influence the results showing a positive rate of TMPRSS2-ERG fusion.

Abstract Background Castrate Resistant Prostate Cancer (CRPC) is an advanced disease resistant to systemic traditional medical or surgical castration, and resistance is primarily attributed to reactivation of AR through multiple mechanisms. TMPRSS2-ERG fusions have been shown to regulate AR signaling, interfere with pro-differentiation functions, and mediate oncogenic signaling. We have recently shown that ERG regulates intra-tumoral androgen synthesis and thereby facilitates AR function in prostate cancer cells. We hypothesize that enzalutamide treatment will be more effective in cells/tumors with TMPRSS2-ERG translocations because these tumors have increased AR signaling. Methods ERG knockdown was performed with VCaP cells using lentiviral infections to generate VCaP ERGshRNA cells and control VCaP scr cells with scrambled shRNA. Cell-growth analysis was performed to determine the effect of enzalutamide. Reverse transcription, quantitative real-time PCR (RT-qPCR) was used to determine the expression of AR responsive genes. Luciferase tagged VCaP scr and shRNA infected cells were used in an intra-tibial animal model for bone tumor growth analysis and enzalutamide treatment used to inhibit AR signaling in bone tumors. Western blotting analyzed VCaP bone tumor samples for ERG, AR, AKR1C3 and HSD3B1 and HSD3B2 expression. Results Enzalutamide inhibited the growth of VCaP scr cells more effectively than shERG cells. Analysis of AR responsive genes shows that Enzalutamide treatment at 5 micromolar concentration inhibited by 85–90% in VCaP Scr cells whereas these genes were inhibited to a lesser extent in VCaP shERG cells. Enzalutamide treatment resulted in severe growth inhibition in VCaP scr shRNA cells compared to VCaP shERG cells. In bone tumor growth experiment, VCaP ERG shRNA cells grew at slower than VCaP scr shRNA cells. Androgen biosynthetic enzyme expression is lower VCaP shERG bone tumors compared to VCaP scr shRNA bone tumors and enzalutamide inhibited the enzyme expression in both types of tumors. Conclusions These data suggest that ERG transcription factor regulates androgen biosynthetic enzyme expression that enzalutamide treatment is more effective against VCaP bone tumors with an intact ERG expression, and that knocking down ERG in VCaP cells leads to a lesser response to enzalutamide therapy. Thus, ERG expression status in tumors could help stratify patients for enzalutamide therapy.

One common genetic alteration in cancer is gene fusion resulting from chromosomal translocations. The mechanisms that create such oncogenic fusion genes are not well understood. Previously, we provided the direct evidence that expression of a designed chimeric RNA can drive the formation of TMPRSS2-ERG gene fusion. Central to this RNA-mediated gene fusion mechanism is a proposed three-way junction formed by RNA/DNA hybrid and the intergenic DNA stem formed by target genes. In this study, we determined the important parameters for chimeric RNA-mediated gene fusion using TMPRSS2-ERG fusion gene as the model. Our results indicate that both the chimeric RNA lengths and the sizes of unpaired bulges play important roles in inducing TMPRSS2-ERG gene fusion. The optimal length of unpaired bulges was about 35 nt, while the optimal chimeric RNA length was about 50 nt for targeting. These observations were consistent regardless of the target locations within TMPRSS2 and ERG genes. These empirically determined parameters provide important insight for searching cellular RNAs that may initiate oncogenic fusion genes. The knowledge could also facilitate the development of useful genomic technology for manipulating mammalian genomes.

Abstract Background Prostate cancer is a major malignancy in males. TMPRSS2-ERG is a high-frequency fusion gene expressed in prostate cancer and plays a vital role in carcinogenesis. Recent studies showed that TMPRSS2-ERG is a potential predictive biomarker for prostate cancer. However, the predictive value of TMPRSS2-ERG fusion is yet unclear. Methods A total of 76 relevant articles, published from 2015 to 2017, were obtained from PubMed, Web of Science, EMBASE, Scopus, the Cochrane Library, and CNKI databases to investigate the predictive significance of TMPRSS2-ERG fusion in prostate cancer. Pooled odds ratio (ORs) with 95% confidence intervals (CIs) were calculated to estimate the correlation between TMPRSS2-ERG fusion gene and tumor features. Results The pooled or stratified analysis showed that the TMPRSS2-ERG fusion gene had a highly predictive potential. First, TMPRSS2-ERG fusion was associated with T-stage at diagnosis (T3–4 vs. T1–2 OR: 1.40; 95% CI 1.33–1.48) and metastasis (M1 vs. M0 OR: 1.35; 95% CI 1.02–1.78) but not with biochemical recurrence or prostate cancer-specific mortality. Furthermore, the subgroup analysis found that the TMPRSS2-ERG fusion gene was correlated with Gleason (G) scores, and the fusion was common in prostate cancer with G ≤ 7. Additionally, the meta-analysis demonstrated that the fusion was likely to occur in young patients (> 65 vs. ≤ 65 OR: 0.68; 95% CI 0.52–0.89), in patients with high PSA levels (> 10 vs. ≤ 10 OR: 1.30; 95% CI 1.21–1.38), and in patients with peripheral involvement (positive vs. negative OR: 1.17; 95% CI 1.08–1.28), while not associated with tumor volume. Finally, the subgroup analysis of different fusion types demonstrated that the deletion-type fusion was significantly associated with the malignant degree of prostate cancer (pooled OR: 5.67; 95% CI 2.85–11.28). Moreover, the deletion-type was common in Africa patients, followed by Caucasian patients, and no significant difference was observed in the incidence of different fusion types in the Asian population. Conclusions The meta-analysis findings suggested that the TMPRSS2-ERG fusion gene might be a predictive marker for prostate cancer patients, and might be valuable for assessing the characteristics of prostate cancer for individualized treatment and prognosis evaluation.

BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones and regulate gene expression. Pharmacological inhibition of BRD4 by BET inhibitors (BETi) has indicated antitumor activity against multiple cancer types. We show that BRD4 is essential for the repair of DNA double-strand breaks (DSBs) and mediates the formation of oncogenic gene rearrangements by engaging the non-homologous end joining (NHEJ) pathway. Mechanistically, genome-wide DNA breaks are associated with enhanced acetylation of histone H4, leading to BRD4 recruitment, and stable establishment of the DNA repair complex. In support of this, we also show that, in clinical tumor samples, BRD4 protein levels are negatively associated with outcome after prostate cancer (PCa) radiation therapy. Thus, in addition to regulating gene expression, BRD4 is also a central player in the repair of DNA DSBs, with significant implications for cancer therapy.

Objective: We examined the immunohistochemical expression of α-methyl acyl coenzyme A racemase (AMACR), CD10, TMPRSS2-ERG, and p27 in prostate adenocarcinoma tumors with different Gleason growth patterns and nonneoplastic prostate tissues to elucidate their roles in prostate carcinogenesis and histological aggressiveness. Material and Methods: In total, 80 archival core biopsy tissues diagnosed as prostate carcinoma, benign prostate hyperplasia, and atrophy cases were included. Immunoreactivity was evaluated by calculating the percentage of positively stained cells and the staining intensity. The mean values and test of significance were obtained using the Kruskal-Wallis test. Results: We obtained mostly intense immunoreactivity for AMACR, CD10, and ERG in adenocarcinomas. Although no significant differences were noted regarding AMACR and ERG expression, samples with Gleason growth patterns 3 and 5 tended to be strongly positive for ERG. Pattern 3 tumors exhibited the weakest positivity for CD10. The p27 expression was strong and diffuse in nonneoplastic prostate tissues. The loss of p27 expression was more frequent for pattern 5 tumors. Conclusion: ERG and AMACR were powerful markers to detect cancer. Especially, ERG is evident in early tumors may reflect its interaction with functional androgen receptors in cancer initiation. Pattern 5 tumors associated with stroma may have been exposed to more stromal substrates and upregulate their CD10 content as a protein degrader. We suggest that CD10 expression is associated with an increasing tumor grade. Decreased concentrations of p27 protein might be implicated in prostate carcinogenesis and may be a useful immunohistochemical adjunct in predicting histological aggressiveness. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is the second cause of cancer related death in North American men. Androgens play an important role in its progression by regulating the expression of several genes including fusion ones that results from structural chromosome rearrangements. TMPRSS2-ERG is a fusion gene commonly observed in over 50% of PCa tumors, and its expression can be transcriptionally regulated by the androgen receptor (AR) given its androgen responsive elements. TMPRSS2-ERG could be involved in epithelial–mesenchymal transition (EMT) during tumor development. ERG has been reported as a key transcriptional factor in the AR-ERG-WNT network where five SFRP proteins, structurally similar to WNT ligands and considered to be WNT pathway antagonists, can regulate signaling in the extracellular space by binding to WNT proteins or Frizzled receptors. It has been shown that over-expression of SFRP1 protein can regulate the transcriptional activity of AR and inhibits the formation of colonies in LNCaP cells. However, the effect of SFRP1 has been controversial since differential effects have been observed depending on its concentration and tissue location. In this study, we explored the role of exogenous SFRP1 protein in cells expressing the TMPRSS2-ERG fusion. Methods: To evaluate the effect of exogenous SFRP1 protein on PCa cells expressing TMPRSS2-ERG, we performed in silico analysis from TCGA cohort, expression assays by RT-qPCR and Western blot, cell viability and cell cycle measurements by cytometry, migration and invasion assays by xCELLigance system and murine xenografts. Results: We demonstrated that SFRP1 protein increased ERG expression by promoting cellular migration in vitro and increasing tumor growth in vivo in PCa cells with the TMPRSS2-ERG fusion. Conclusions: These results suggest the possible role of exogenous SFRP1 protein as a modulator of AR-ERG-WNT signaling network in cells positive to TMPRSS2-ERG. Further, investigation is needed to determine if SFRP1 protein could be a target in against this type of PCa. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PC) can display very heterogeneous phenotypes ranging from indolent asymptomatic to aggressive lethal forms. Understanding how these PC subtypes vary in their striving for energy and anabolic molecules is of fundamental importance for developing more effective therapies and diagnostics. Here, we carried out an extensive analysis of prostate tissue samples to reveal metabolic alterations during PC development and disease progression and furthermore between TMPRSS2-ERG rearrangement-positive and -negative PC subclasses.Methods: Comprehensive metabolomics analysis of prostate tissue samples was performed by non-destructive high-resolution magic angle spinning nuclear magnetic resonance (1H HR MAS NMR). Subsequently, samples underwent moderate extraction, leaving tissue morphology intact for histopathological characterization. Metabolites in tissue extracts were identified by 1H/31P NMR and liquid chromatography-mass spectrometry (LC-MS). These metabolomics profiles were analyzed by chemometric tools and the outcome was further validated using proteomic data from a separate sample cohort.Results: The obtained metabolite patterns significantly differed between PC and benign tissue and between samples with high and low Gleason score (GS). Five key metabolites (phosphocholine, glutamate, hypoxanthine, arginine and α-glucose) were identified, who were sufficient to differentiate between cancer and benign tissue and between high to low GS. In ERG-positive PC, the analysis revealed several acylcarnitines among the increased metabolites together with decreased levels of proteins involved in β-oxidation; indicating decreased acyl-CoAs oxidation in ERG-positive tumors. The ERG-positive group also showed increased levels of metabolites and proteins involved in purine catabolism; a potential sign of increased DNA damage and oxidative stress.Conclusions: Our comprehensive metabolomic analysis strongly indicates that ERG-positive PC and ERG-negative PC should be considered as different subtypes of PC; a fact requiring different, sub-type specific treatment strategies for affected patients. [ABSTRACT FROM AUTHOR]

In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2‐ERG (T2E)‐fusion oncoproteins defining two molecular subtypes (T2E‐positive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate gene‐signatures associated with metastasis in T2E‐positive and T2E‐negative PCa independently, we integrated tumor transcriptomes and clinicopathological data of two cohorts (total n = 783), and analyzed metastasis‐associated gene‐signatures regarding the T2E‐status. Here, we show that the prognostic value of biomarkers in PCa critically depends on the T2E‐status. Using gene‐set enrichment analyses, we uncovered that metastatic T2E‐positive and T2E‐negative PCa are characterized by distinct gene‐signatures. In addition, by testing genes shared by several functional gene‐signatures for their association with event‐free survival in a validation cohort (n = 272), we identified five genes (ASPN, BGN, COL1A1, RRM2 and TYMS)—three of which are included in commercially available prognostic tests—whose high expression was significantly associated with worse outcome exclusively in T2E‐negative PCa. Among these genes, RRM2 and TYMS were validated by immunohistochemistry in another validation cohort (n = 135), and several of them proved to add prognostic information to current clinicopathological predictors, such as Gleason score, exclusively for T2E‐negative patients. No prognostic biomarkers were identified exclusively for T2E‐positive tumors. Collectively, our study discovers that the T2E‐status, which is per se not a strong prognostic biomarker, crucially determines the prognostic value of other biomarkers. Our data suggest that the molecular subtype needs to be considered when applying prognostic biomarkers for outcome prediction in PCa. What's new? Genetic rearrangements involving androgen‐regulated transmembrane protease serine 2 and genes from the ETS transcription factor family (T2E), most commonly ERG and ETV1, occur in half of prostate cancers but are currently not considered in risk predictions. The authors integrate clinical and transcriptomic data from multiple studies and show that the prognostic value of biomarkers critically depends on the T2E‐status. They identify five biomarkers that predict negative outcome exclusively in T2E‐negative prostate cancers, which has implications for outcome prediction based on the molecular subtype. [ABSTRACT FROM AUTHOR]

Introduction: 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. Discussion: The results from this research are in accordance with the values and results from analyses done in several research centres and oncological institutes. [ABSTRACT FROM AUTHOR]

Abstract Background Prostate cancer (PCa) is characterized by clinical and biological heterogeneity and has differential outcomes and mortality rates. Therefore, it is necessary to identify molecular alterations to define new therapeutic strategies based on the risk of progression. In this study, the prognostic relevance of the insulin-like growth factor (IGF) system was examined in molecular subtypes defined by TMPRSS2-ERG (T2E) gene fusion within a series of patients with primary localized PCa. Methods A cohort of 270 formalin-fixed and paraffin-embedded (FFPE) primary PCa samples from patients with more than 5 years’ follow-up was collected. IGF-1R, IGF-1, IGFBP-3 and INSR expression was analyzed using quantitative RT-PCR. The T2E status and immunohistochemical ERG findings were considered in the analyses. The association with both biochemical and clinical progression-free survival (BPFS and PFS, respectively) was evaluated for the different molecular subtypes using the Kaplan-Meier proportional risk log-rank test and the Cox proportional hazards model. Results An association between IGF-1R overexpression and better BPFS was found in T2E-negative patients (35.3% BPFS, p-value = 0.016). Multivariate analysis demonstrated that IGF-1R expression constitutes an independent variable in T2E-negative patients [HR: 0.41. CI 95% (0.2–0.82), p = 0.013]. These data were confirmed using immunohistochemistry of ERG as subrogate of T2E. High IGF-1 expression correlated with prolonged BPFS and PFS independent of the T2E status. Conclusions IGF-1R, a reported target of T2E, constitutes an independent factor for good prognosis in T2E-negative PCa. Quantitative evaluation of IGF-1/IGF-1R expression combined with molecular assessment of T2E status or ERG protein expression represents a useful marker for tumor progression in localized PCa.

Older age is one of the main risk factors for cancer development. The incidence of prostate cancer, as a multifactorial disease, also depends upon demographic factors, race, and genetic predisposition. Prostate cancer most frequently occurs in men over 60 years of age, indicating a clear association between older age and disease onset. Carcinogenesis is followed by the deregulation of many genes, and some of these changes could serve as biomarkers for diagnosis, prognosis, prediction of drug therapy efficacy, as well as possible therapeutic targets. We have performed a bioinformatic analysis of a The Cancer Genome Atlas (TCGA) data and RNA-Seq profiling of a Russian patient cohort to reveal prognostic markers of locally advanced lymph node-negative prostate cancer (lymph node-negative LAPC). We also aimed to identify markers of the most common molecular subtype of prostate cancer carrying a fusion transcript TMPRSS2-ERG. We have found several genes that were differently expressed between the favorable and unfavorable prognosis groups and involved in the enriched KEGG pathways based on the TCGA (B4GALNT4, PTK6, and CHAT) and Russian patient cohort data (AKR1C1 and AKR1C3). Additionally, we revealed such genes for the TMPRSS2-ERG prostate cancer molecular subtype (B4GALNT4, ASRGL1, MYBPC1, RGS11, SLC6A14, GALNT13, and ST6GALNAC1). Obtained results contribute to a better understanding of the molecular mechanisms behind prostate cancer progression and could be used for further development of the LAPC prognosis marker panel.

TMPRSS2‐ERG expression in blood has been correlated with low docetaxel benefit in metastatic castration‐resistant prostate cancer (mCRPC). This multicenter study aimed to prospectively asses its role as a taxane‐resistance biomarker in blood and retrospectively in tumors, exploring also the impact of prior abiraterone/enzalutamide (A/E) in patients and in vitro. TMPRSS2‐ERG was tested by quantitative reverse‐transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2‐ERG expression was correlated with prostate‐specific antigen (PSA)‐progression‐free survival (PFS), radiological‐PFS (RX‐PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. In vitro ERG knockdown and combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Prior A/E (HR 1.8, 95% CI 1.2–2.8) and blood TMPRSS2‐ERG detection (HR 2, 95% CI 1.1–3.7) were independently associated to lower PSA‐PFS. In patients without prior A/E, blood and tumor TMPRSS2‐ERG independently predicted lower PSA‐PFS (HR 3.3, 95% CI 1.4–7.9 and HR 1.8, 95% CI 1.02–3.3, respectively) to taxanes. When prior A/E was administered, TMPRSS2‐ERG was not associated with outcome. There was a significant interaction between blood TMPRSS2‐ERG and prior A/E related to PSA‐PFS (p = 0.032) and RX‐PFS (p = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced the expression of neuroendocrine markers and reduced that of E‐cadherin. We conclude that prior hormone‐therapy may influence taxanes response and TMPRSS2‐ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow‐up evaluation. What's new? Despite known resistance mechanisms, no molecular biomarkers to predict taxane resistance are clinically available. TMPRSS2‐ERG rearrangement is a prostate cancerspecific genetic alteration known to impair taxane sensitivity in preclinical models. This study shows that blood and tumour TMPRSS2‐ERG expression independently predicted lower prostate‐specific antigen progression‐free survival in metastatic castration‐resistant prostate cancer (mCRPC) patients following taxanes. When prior abiraterone/ enzalutamide therapy was administered, TMPRSS2‐ERG was not associated with outcome. Prior hormone‐therapy may influence taxane response and TMPRSS2‐ERG prognostic value, suggesting the need for multiple and sequential biomarkers in mCRPC follow‐up evaluation. [ABSTRACT FROM AUTHOR]

Older age is one of the main risk factors for cancer development. The incidence of prostate cancer, as a multifactorial disease, also depends upon demographic factors, race, and genetic predisposition. Prostate cancer most frequently occurs in men over 60 years of age, indicating a clear association between older age and disease onset. Carcinogenesis is followed by the deregulation of many genes, and some of these changes could serve as biomarkers for diagnosis, prognosis, prediction of drug therapy efficacy, as well as possible therapeutic targets. We have performed a bioinformatic analysis of a The Cancer Genome Atlas (TCGA) data and RNA-Seq profiling of a Russian patient cohort to reveal prognostic markers of locally advanced lymph node-negative prostate cancer (lymph node-negative LAPC). We also aimed to identify markers of the most common molecular subtype of prostate cancer carrying a fusion transcript TMPRSS2-ERG. We have found several genes that were differently expressed between the favorable and unfavorable prognosis groups and involved in the enriched KEGG pathways based on the TCGA (B4GALNT4 , PTK6 , and CHAT) and Russian patient cohort data (AKR1C1 and AKR1C3). Additionally, we revealed such genes for the TMPRSS2-ERG prostate cancer molecular subtype (B4GALNT4 , ASRGL1 , MYBPC1 , RGS11 , SLC6A14 , GALNT13 , and ST6GALNAC1). Obtained results contribute to a better understanding of the molecular mechanisms behind prostate cancer progression and could be used for further development of the LAPC prognosis marker panel. [ABSTRACT FROM AUTHOR]

Prostate cancer is a kind of male malignancy. Recently, a large number of studies have reported many potential biomarkers for the diagnosis and prognosis of prostate cancer. In this literature review, we have collected a number of potential biomarkers for prostate cancer reported in the last 5 years. Among them, some are undergoing Phase III clinical trials, and others have been approved by the US Food and Drug Administration. However, most are still in the period of basic research. The review will contribute to future research to find the biomarkers to guide clinicians to make personalized treatment decisions for each prostate cancer patient. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is one of the primary causes of cancer-related mortality in men worldwide. Patients with locally advanced PCa with metastases in regional lymph nodes are usually marked as a high-risk group. One of the chief concerns for this group is to make an informed decision about the necessity of conducting adjuvant androgen deprivation therapy after radical surgical treatment. During the oncogenic transformation and progression of the disease, the expression of many genes is altered. Some of these genes can serve as markers for diagnosis, predicting the prognosis or effectiveness of drug therapy, as well as possible therapeutic targets. We undertook bioinformatic analysis of the RNA-seq data deposited in The Cancer Genome Atlas consortium database to identify possible prognostic markers. We compared the groups with favorable and unfavorable prognosis for the cohort of patients with PCa showing lymph node metastasis (pT2N1M0, pT3N1M0, and pT4N1M0) and for the most common molecular type carrying the fusion transcript TMPRSS2-ERG. For the entire cohort, we revealed at least six potential markers (IDO1, UGT2B15, IFNG, MUC6, CXCL11, and GBP1). Most of these genes are involved in the positive regulation of immune response. For the TMPRSS2-ERG subtype, we also identified six genes, the expression of which may be associated with prognosis: TOB1, GALNT7, INAFM1, APELA, RAC3, and NNMT. The identified genes, after additional studies and validation in the extended cohort, could serve as a prognostic marker of locally advanced lymph node-positive PCa. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Prostate cancer is a heterogenous disease and the mechanisms that drive it to behave differently are not well understood. Tumour expression of the ERG oncogene occurs in the majority of patients with prostate cancer in Western studies. This is considered to be oncogenic as ERG acts as a transcription factor to regulate genes involved in tumour proliferation and invasion. In this study we investigated expression of ERG in Malaysian men with prostate cancer. Methods: Tissues were collected from 80 patients with clinically detected prostate cancer and treated with radical prostatectomy. Cases were tested for ERG by immunohistochemistry using the mouse monoclonal antibody EP111. All blocks on 48 cases were tested in order to determine the extent of heterogeneity of ERG expression within individual cases. ERG expression was analysed in relation to patient age, ethnicity and tumour stage and grade. Results: Forty-six percent of cases were ERG positive. There was no significant association between ERG and tumour grade or stage. Sixty-nine percent of Indian patients had ERG positive tumours; this was significantly higher (p=0.031) than for Chinese (40%) and Malay (44%) patients. Heterogeneity of ERG expression, in which both positive and negative clones were present, was seen in 35% of evaluated cases. Evaluation by tumour foci showed younger patients had more ERG positive tumour foci than older patients (p=0.01). Indian patients were more likely to have the majority of tumour foci with ERG staining positively, compared to either Chinese or Malay patients (P <0.01). Conclusion: In this study, tumour expression of ERG was more likely to occur in patients of Indian ethnicity. [ABSTRACT FROM AUTHOR]

Genetic rearrangements involving androgen-regulated transmembrane protease serine 2 ( TMPRSS2 ) and genes from the ETS transcription factor family, most commonly ERG and ETV1 , result in alteration that responsible for oncogenic activity in prostate cancer (PC). The aims of the present study were to: 1) investigate the frequency of these fusion transcripts in prostate tissue samples obtained from patients diagnosed with atypical small acinar proliferation (ASAP), 2) determine any clinical significance of T2E expression at the RNA level in predicting PC detection in subsequent biopsies, and 3) evaluate expression of the PC marker, alpha-methylacyl-CoA racemase ( AMACR ), according to T2E status by real-time quantitative reverse transcription PCR (RT-qPCR). T2E transcripts were detected in 31.7% ( n = 20) of the patients examined, and this was significantly associated with subsequent detection of PC in ASAP patients with a prostate specific antigen (PSA) level of 4–10 ng/ml ( p = 0.045). AMACR expression was also significantly higher in the patients who were diagnosed with PC in subsequent biopsies than in the patients who were not diagnosed with PC ( p = 0.034) and in T2E -positive ASAP patients ( p = 0.002) compared to T2E -negative ASAP patients. Although these results need to be further clinically validated, we suggest that the presence of T2E transcript, in association with higher AMACR expression, is an indicator of PC risk from a T2E -positive focus or an unsampled malignant gland adjacent to a T2E -positive site in ASAP lesions. [ABSTRACT FROM AUTHOR]

BackgroundEpidemiologic evidence shows that obesity is associated with a greater risk of aggressive prostate cancer (PCa) and PCa-specific mortality and this is observed mainly in men with the TMPRSS2-ERG gene fusion. Obesity is often associated with comorbid conditions such as type 2 diabetes and hyperglycemia: we investigated whether some of the exposures associated with disturbed metabolism can also affect the frequency of this gene fusion.MethodsFusion was induced in LNCaP PCa cells in normal or high levels of glucose, with or without insulin-like growth factor binding protein-2 (IGFBP-2) silenced or the presence of insulin-like growth factor-1 (IGF-I), insulin, or epidermal growth factor (EGF). RNA was extracted for analysis by nested PCR. Abundance of IGFBP-2, γH2AX, DNA-dependent protein kinase catalytic subunit (DNAPKcs), and β-actin were analyzed by Western immunoblotting.ResultsOur data suggest that hyperglycemia-induced IGFBP-2 increased the frequency of the gene fusion that was accompanied by decreased levels of DNAPKcs implying that they were mediated by alterations in the rate of repair of double-strand breaks. In contrast insulin, IGF-I and EGF all decreased gene fusion events.ConclusionThese novel observations may represent a further mechanism by which obesity can exert an effect aggravating PCa progression.

Background: Epidemiologic evidence shows that obesity is associated with a greater risk of aggressive prostate cancer (PCa) and PCa-specific mortality and this is observed mainly in men with the TMPRSS2-ERG gene fusion. Obesity is often associated with comorbid conditions such as type 2 diabetes and hyperglycemia: we investigated whether some of the exposures associated with disturbed metabolism can also affect the frequency of this gene fusion. Methods: Fusion was induced in LNCaP PCa cells in normal or high levels of glucose, with or without insulin-like growth factor binding protein-2 (IGFBP-2) silenced or the presence of insulin-like growth factor-1 (IGF-I), insulin, or epidermal growth factor (EGF). RNA was extracted for analysis by nested PCR. Abundance of IGFBP-2, γH2AX, DNA-dependent protein kinase catalytic subunit (DNAPKcs), and β-actin were analyzed by Western immunoblotting. Results: Our data suggest that hyperglycemia-induced IGFBP-2 increased the frequency of the gene fusion that was accompanied by decreased levels of DNAPKcs implying that they were mediated by alterations in the rate of repair of double-strand breaks. In contrast insulin, IGF-I and EGF all decreased gene fusion events. Conclusion: These novel observations may represent a further mechanism by which obesity can exert an effect aggravating PCa progression. [ABSTRACT FROM AUTHOR]

Identifying genetic diversity is important for studies in cancer as it can provide insights on disease progression and treatment. Although clinical outcome and major symptom of cancer might be same in all patients, the type of overexpressed gene could be different. Even though prostate-specific antigen assay is a good tool widely used for prostate cancer diagnosis, it is not capable of providing information on genetic differences. Therefore, screening method that can differentiate genetic differences is necessary. Here we detected different types of TMPRSS2-ERG, prostate cancer specific fusion genes, to verify the genetic diversity between the patients using high throughput screening method, bio-barcode assay. Prostate cancer patients with different types of fusion gene were successfully differentiated directly from untreated patients' urine, while traditional PSA assay could not. This non-invasive assay, when used with PSA assay, can be a strong secondary screening method which can offer new insights on disease progression and clinical outcome. [ABSTRACT FROM AUTHOR]

Introduction: Treatment planning in patients with prostate neoplasms and prostate cancer (PCa) is generally based on the clinical and pathological molecular markers obtained from prostate needle biopsy and/or radical prostatectomy specimens. Area covered: Pathology of prostate neoplasms is evolving rapidly. Emerging trends include new additions to the 2016 World Health Organization (WHO) tumor classification as well as expanded diagnostic utility of biomarkers and molecular testing in tissue specimens, liquid biopsies and urinary samples, with the following purposes: diagnosis, prognosis and prediction. Expert commentary: The new additions to the 2016 WHO tumor classification, which include pathological definition of Intraductal carcinoma of the prostate (IDC-P) and of a new grading system for PCa, as well as identification of molecular markers, such asTMPRSS2-ERGandAR-V7, may pave the way to personalized therapy for patients with prostate tumors. [ABSTRACT FROM PUBLISHER]

Background: Prostate cancer (PCa) is characterized by clinical and biological heterogeneity and has differential outcomes and mortality rates. Therefore, it is necessary to identify molecular alterations to define new therapeutic strategies based on the risk of progression. In this study, the prognostic relevance of the insulin-like growth factor (IGF) system was examined in molecular subtypes defined by TMPRSS2-ERG (T2E) gene fusion within a series of patients with primary localized PCa.Methods: A cohort of 270 formalin-fixed and paraffin-embedded (FFPE) primary PCa samples from patients with more than 5 years' follow-up was collected. IGF-1R, IGF-1, IGFBP-3 and INSR expression was analyzed using quantitative RT-PCR. The T2E status and immunohistochemical ERG findings were considered in the analyses. The association with both biochemical and clinical progression-free survival (BPFS and PFS, respectively) was evaluated for the different molecular subtypes using the Kaplan-Meier proportional risk log-rank test and the Cox proportional hazards model.Results: An association between IGF-1R overexpression and better BPFS was found in T2E-negative patients (35.3% BPFS, p-value = 0.016). Multivariate analysis demonstrated that IGF-1R expression constitutes an independent variable in T2E-negative patients [HR: 0.41. CI 95% (0.2-0.82), p = 0.013]. These data were confirmed using immunohistochemistry of ERG as subrogate of T2E. High IGF-1 expression correlated with prolonged BPFS and PFS independent of the T2E status.Conclusions: IGF-1R, a reported target of T2E, constitutes an independent factor for good prognosis in T2E-negative PCa. Quantitative evaluation of IGF-1/IGF-1R expression combined with molecular assessment of T2E status or ERG protein expression represents a useful marker for tumor progression in localized PCa. [ABSTRACT FROM AUTHOR]

Objectives To assess time to progression to castrate-resistant prostate cancer ( CRPC) and factors influencing longer-term outcomes in patients receiving androgen-deprivation therapy ( ADT) in an extension to the Triptocare study ( NCT01020448). This is pertinent as the Triptocare study did not show that urinary prostate cancer antigen-3 (PCA3) score was a reliable marker of cancer stage in advanced prostate cancer and was not useful for assessing response 6 months after initiation of ADT with triptorelin 22.5 mg. Patients and Methods An international, multicentre, non-interventional, observational, longitudinal, prospective study involving patients from the Triptocare study. CRPC status of patients was collected for up to 3 years from ADT initiation. Patient treatment and assessments were at the investigator's discretion. Co-primary endpoints were rate of CRPC at 3 years after initiating ADT and the median time to CRPC. An exploratory endpoint was the association of Triptocare baseline variables (including TMPRSS2- ERG and PCA3 scores) and PCA3 score at Triptocare last value available with CRPC onset. Results Of the 325 patients in the Triptocare study safety population, 180 patients were enrolled in the Triptocare LT study (102 received continuous and 78 received intermittent ADT). CRPC rates at 3 years were 24/102 (23.5%) and 6/78 (7.7%) patients in the continuous and intermittent ADT groups, respectively. The median time to CRPC was not reached for either group. PCA3 score status at baseline was the only variable associated with a higher risk of progression to CRPC in both the intermittent and continuous ADT groups; compared with a baseline PCA3 score of ≥35, a PCA3 score below the level of quantification had a hazard ratio ( HR) of 20.04 ([95% confidence interval ( CI) 2.71-148.34] and a HR of 9.44 [95% CI 2.39-37.27], respectively). Baseline metastatic disease and testosterone level were additionally associated with progression to CRPC in the continuous ADT population ( HR 5.20, 95% CI 1.68-16.06 and HR 0.995, 95% CI 0.991-0.999, respectively). Conclusion In men with locally advanced or metastatic prostate cancer, a PCA3 score of ≥35 at the time of initiating ADT may predict a lower risk of developing CRPC in the following 3 years. [ABSTRACT FROM AUTHOR]

Summary Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation-specific (ETS) transcription factor ERG . The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation-induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by non-homologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli lead to the development of prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Men of African ancestry have disproportionately high incidence rates of prostate cancer (PCa) and have high mortality rates. While there is evidence for a higher genetic predisposition for incidence of PCa in men of African ancestry compared to men of European ancestry, there have been few transcriptomic studies on PCa in men of African ancestry in the African continent., Objective: We performed transcriptomic profiling and fusion analysis on bulk RNA sequencing (RNA-seq) samples from 24 Nigerian PCa patients to investigate the transcriptomic and genomic rearrangement landscape of PCa in Nigerian men., Design: Bulk RNA-seq was performed on 24 formalin-fixed paraffin-embeded (FFPE) prostatectomy specimens of Nigerian men. Transcriptomic analysis was performed on 11 high-quality samples. Arriba Fusion and STAR Fusion were used for fusion detection., Results: 4/11 (36%) of the samples harbored an erythroblast transformation-specific (ETS) fusion event; 1/11 (9%) had a TMPRSS2-ERG fusion; 2/11 had a TMPRSS2-ETV5 fusion, and 1/11 had a SLC45A3-SKIL fusion. Hierarchical clustering of normalized and mean-centered gene expression showed clustering of fusion positive samples. Furthermore, we developed gene set signatures for Nigerian PCa based on fusion events. By projecting the cancer genome atlas prostate adenocarcinoma (TCGA-PRAD) bulk RNA-seq data set onto the transcriptional space defined by these signatures derived from Nigerian PCa patients, we identified a positive correlation between the Nigerian fusion signature and fusion positive samples in the TCGA-PRAD data set., Conclusions: Less frequent ETS fusion events other than TMPRSS2-ERG such as TMPRSS2-ETV5 and non-ETS fusion events such as SLC45A3-SKIL may be more common in PCa in Nigerian men. This study provides useful working transcriptomic signatures that characterize oncogenic states representative of specific gene fusion events in PCa from Nigerian men., (© 2023 Wiley Periodicals LLC.)