BACKGROUND: Prostate cancer (PCa) is the second most commonly diagnosed cancer in men. To date, the role of the combined application of long non-coding RNAs (PCA3, DLX1, HOXC6, TMPRSS2:ERG) for obtaining the most accurate method of detection of PCa has not yet been comprehensively investigated. METHODS: In total 240 persons were included in the retrospective study. Among them were 150 patients with confirmed PCa, 30 patients with benign prostatic hyperplasia, 30 patients with active chronic prostatitis and 30 healthy volunteers. In all patients, the urine samples were collected prior to biopsy or treatment. Polymerase chain reaction with reverse transcription was performed to detect the expression level of PCA3, HOXC6, DLX1 and the presence of the TMPRSS2:ERG transcript. RESULTS: PCA3 was detected in urine samples in all cases. Using a PCA3 score of 56 allowed the differentiation between PCa and all other cases with a sensitivity of 61% and specificity of 96% (p < 0.001) while a PCA3 score threshold value of 50 resulted in a differentiation between clinically significant PCa (ISUP grades 2-5) and all other cases with a sensitivity of 93% and specificity of 93% (p < 0.001). The TMPRSS2:ERG expression in urine was detected exclusively in the group of patients with PCa and only in 16% of all cases. CONCLUSIONS: PCA3 score detected in urine demonstrated moderate sensitivity and good specificity in differentiation between PCa and non-PCa and high sensitivity and specificity in differentiation between clinically significant PCa and non-PCa.
- MeSH
- Antigens, Neoplasm * genetics MeSH
- Oncogene Proteins, Fusion genetics urine MeSH
- Homeodomain Proteins genetics MeSH
- Humans MeSH
- Biomarkers, Tumor urine MeSH
- Prostatic Neoplasms * diagnosis genetics MeSH
- Prostate pathology MeSH
- Prostate-Specific Antigen MeSH
- Retrospective Studies MeSH
- Serine Endopeptidases genetics MeSH
- Transcriptional Regulator ERG MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
AIMS: To evaluate the molecular underpinnings of the rare aggressive prostate cancer variants adenosquamous carcinoma, pleomorphic giant-cell carcinoma, and sarcomatoid carcinoma. METHODS AND RESULTS: We retrieved 19 tumours with one or more variant(s), and performed ERG immunohistochemistry, a next-generation sequencing assay targeting recurrent gene fusions, and fluorescence in-situ hybridisation (FISH) for ERG and BRAF. Divergent differentiation included: sarcomatoid carcinoma (n = 10), adenosquamous carcinoma (n = 7), and pleomorphic giant-cell carcinoma (n = 7). Five patients had more than one variant. Four had variants only in metastases. ERG rearrangement was detected in nine (47%, seven via sequencing, showing TMPRSS2-ERG fusions and one GRHL2-ERG fusion, and two via FISH, showing rearrangement via deletion). ERG was immunohistochemically positive in the adenocarcinoma in eight of nine (89%) patients, but was immunohistochemically positive in the variant in only five of nine patients (56%, typically decreased). One patient had a false-positive ERG immunohistochemical result in the sarcomatoid component despite a negative FISH result. Two (11%) harboured BRAF fusions (FAM131A-BRAF and SND1-BRAF). CONCLUSIONS: ERG fusions are present in these rare prostate cancer variants with a frequency close to that in conventional prostate cancer (9/19, 47%). ERG immunohistochemistry usually detects rearrangement in the adenocarcinoma, but is less sensitive for the variant histology, with weak to negative staining. Adenosquamous and sarcomatoid variants can, particularly, occur together. Molecular assessment may be an additional tool in selected cases to confirm the prostatic origin of unusual tumours. The presence of two BRAF rearrangements suggests that this gene fusion may be enriched in this setting, as RAF kinase fusions have been previously reported in 1-2% of prostate cancers.
- MeSH
- Carcinoma, Adenosquamous genetics pathology MeSH
- DNA-Binding Proteins genetics metabolism MeSH
- Gene Fusion * MeSH
- Oncogene Proteins, Fusion genetics MeSH
- Gene Rearrangement MeSH
- In Situ Hybridization, Fluorescence MeSH
- Immunohistochemistry MeSH
- Carcinoma, Renal Cell genetics pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Metastasis genetics pathology MeSH
- Prostatic Neoplasms genetics pathology MeSH
- Carcinoma, Giant Cell genetics pathology MeSH
- Proto-Oncogene Proteins B-raf genetics metabolism MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Serine Endopeptidases genetics MeSH
- Transcription Factors genetics metabolism MeSH
- Transcriptional Regulator ERG genetics metabolism MeSH
- High-Throughput Nucleotide Sequencing MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
Východiska: Cílem studie byla detekce CD204+ a CD3+ buněk v infiltrátu struktur benigní prostatické hyperplazie, prostatické intraepitelové neoplazie a prostatického karcinomu ve vzorcích prostaty po radikální prostatektomii a korelace intenzity této infiltrace s expresí onkoproteinu ERG i výskytem ERG aktivující translokace TMPRSS2-ERG. Materiál a metody: Detekce translokace byla provedena pomocí fluorescenční in situ hybridizace, detekce onkoproteinu ERG a fenotypu infiltrujících buněk byly provedeny imunohistochemicky. Případy byly dále rozděleny do podsouborů podle stupně infiltrace a rozdílů v infiltraci benigních a maligních struktur prostaty. Výsledky: Biometrická analýza potvrdila, že množství CD204+ makrofágů v infiltrátu maligních struktur se významně zvyšuje, a to bez ohledu na fúzní stav. Infiltrace CD3+ buňkami se v maligních strukturách zvyšovala pouze u případů s normálním stavem i u případů s prokázanou genovou fúzí. Exprese ERG pozitivně korelovala s infiltrací nádorového stromatu CD204+ makrofágy i CD3+ lymfocyty jen u případů s prokázaným fúzním genem. U případů s prokázanou přestavbou TMPRSS2 genu bez existence fúzního genu byla pozitivní korelace prokázána jen mezi expresí ERG a infiltrací CD204+ makrofágy. U negativních případů žádná korelace prokázána nebyla. Dále se ukázalo, že ve skupině s prokázaným fúzním genem je významně více případů s dobrou reaktivitou CD204+ buněk a ve skupině negativní naopak více případů se slabou reaktivitou CD204+ buněk. Stejný korelační vztah byl pozorován i v případě CD3+ T lymfocytů. CD204+ makrofágy i CD3+ T lymfocyty u případů s prokázaným fúzním genem tak infiltrovaly maligní struktury prostaty intenzivněji. Jejich funkce při malignizaci však je pravděpodobně rozdílná. Závěr: Tato asociace mezi přítomností fúzního genu TMPRSS2-ERG a rozdílnou schopností některých zánětlivých buněk infiltrovat maligní struktury v prostatě nebyla dosud popsána. Výsledky potvrzují důležitou úlohu aktivovaného genu ERG při rozvoji zánětu v prostatě, stejně jako vliv zánětlivých buněk na rozvoj neoplastického procesu. Současně nabízejí možnost úvah o zařazení imunomodulačních postupů do terapeutického portfolia karcinomů prostaty
Background: The aim of the study was to detect CD204+ and CD3+ cells in the infiltrate of benign prostatic hyperplasia, prostatic intraepithelial neoplasia and prostatic cancer in prostate specimens after radical prostatectomy. Another goal was to determine correlation of the intensity of the infiltration with ERG oncoprotein expression as well as with the presence of activating translocation TMPRSS2-ERG. Materials and Methods: To confirm the translocation, we used fluorescence in situ hybridization. Imunohistochemistry was used to detect the presence of ERG oncoprotein and for assesment of the number of CD204+ and CD3+ infiltrating cells. We determined the capability to infiltrate malignant structures according to differences in infiltration of benign and malignant prostate structures. Results: Biometric analysis confirmed that the number of CD204+ macrophages in the malignant structure was significantly higher than in the benign prostatic hyperplasia regardless of the fusion pattern. Increased infiltration by CD3+ cells was only detected in malignant structures of the prostate in a group with normal signal pattern and in a with TMPRSS2-ERG fusion. Expression of ERG positively correlated with CD204+ and CD3+ cells infiltration of malignant structures only in cases where the TMPRSS2-ERG fusion was found. In the group with a break in the TMPRSS2 gene, a positive correlation was only found between ERG expression and CD204+ macrophages infiltration. In cases with a normal signal pattern, no correlation was found. In the group with TMPRSS2-ERG fusion we observed significantly more cases with a good capability of CD204+ cells to infiltrate malignant structures, unlike the group with a normal signal pattern, where there were more cases with the weak reactivity of CD204+ cells to infiltrate the malignant structures. The same was observed for CD3+ cells. CD204+ macrophages and CD3+ T-lymphocytes in the group with TMPRSS2-ERG gene fusion, infiltrated the malignant prostate structures more intensely, but their effect on malignant transformation may be different. Conclusions: The association between the presence of the TMPRSS2-ERG fusion and the different capability of inflammatory cells to infiltrate malignant structures has not been reported so far. The results confirm the important role of the activated ERG gene, due to TMPRSS2-ERG fusion, in the development of inflammation of the prostate as well as the effect of inflammatory cells on the course of neoplastic process. This leads to considerations about introducing immunomodulatory modalities into prostate cancer therapeutic protocols. lymphocytes.
A number of prostate cancer (PCa)-specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor olaparib used as single agent for treatment of metastatic castration-resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa, we evaluated a potential use for olaparib in combination with first-line endocrine treatments, androgen deprivation, and complete androgen blockade, and as a maintenance therapy following on from endocrine therapy. We demonstrate that the LNCaP cell line, possessing multiple aberrations in BRCAness genes, is sensitive to olaparib. Additive effects of olaparib combined with endocrine treatments in LNCaP are noted. In contrast, we find that the TMPRSS2:ERG fusion-positive cell lines VCaP and DuCaP do not show signs of synthetic lethality, but are sensitive to cytotoxic effects caused by olaparib. In consequence, additive effects of olaparib with endocrine therapy were not observable in these cell lines, showing the need for synthetic lethality in combination treatment regimens. Additionally, we show that PCa cells remain sensitive to olaparib treatment after initial androgen deprivation implicating a possible use of olaparib as maintenance therapy. In sum, our preclinical data recommend olaparib as a synthetic lethal treatment option in combination or sequenced to first-line endocrine therapy for PCa patients with diagnosed BRCAness.
- MeSH
- Androgens metabolism MeSH
- Models, Biological * MeSH
- Phthalazines pharmacology MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Prostatic Neoplasms, Castration-Resistant * metabolism pathology therapy MeSH
- Piperazines pharmacology MeSH
- Maintenance Chemotherapy methods MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND/AIM: Current research of prostate cancer (PCa) offers a promising way of identifying patients with adverse prognosis who do benefit from radical treatment that can affect quality of life as resections are associated with numerous side-effects. The aim of our study was to evaluate the relationship of TMPRSS2-ERG fusion gene status, tumor tissue prostate-specific antigen (PSA), prostate cancer antigen 3 (PCA3), miR-23b, miR-26a and miR-221 expression levels in combination with preoperative serum PSA level to the risk of PCa recurrence after radical prostatectomy. PATIENTS AND METHODS: The study group consisted of 108 patients who underwent radical prostatectomy. PSA was measured in peripheral blood collected preoperativelly. The expression of TMPRSS2-ERG transcript and the expression of miR-23b, miR-26a and miR-221 in formalin-fixed, paraffin-embedded (FFPE) tumor tissues was analyzed by reverse transcription (RT) real-time polymerase chain reaction (PCR). RESULTS: Significantly shorter time to recurrence was observed in patients with high expression of TMPRSS2-ERG (p=0.0020). High levels of preoperative PSA (>10.0 ng/ml) proved to be marker of shorter time to recurrence (p=0.0153). The most promising marker of the risk of recurrence after radical prostatectomy was a combination of high level of preoperative serum PSA and high expression of TMPRSS2-ERG fusion transcript in tumor tissue (p=0.0001). CONCLUSION: A combination of high preoperative serum PSA and high expression of TMPRSS2-ERG could be promising in distinguishing those tumors that are aggressive and life-threatening.
- MeSH
- Antigens, Neoplasm biosynthesis genetics MeSH
- Adult MeSH
- Oncogene Proteins, Fusion genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Recurrence, Local blood genetics pathology MeSH
- MicroRNAs biosynthesis genetics MeSH
- Biomarkers, Tumor biosynthesis blood genetics MeSH
- Prostatic Neoplasms blood genetics pathology surgery MeSH
- Predictive Value of Tests MeSH
- Prognosis MeSH
- Proportional Hazards Models MeSH
- Prostate pathology MeSH
- Prostatectomy MeSH
- Prostate-Specific Antigen blood MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Risk Factors MeSH
- Aged MeSH
- Paraffin Embedding MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
The DNA damage checkpoints provide an anti-cancer barrier in diverse tumour types, however this concept has remained unexplored in prostate cancer (CaP). Furthermore, targeting DNA repair defects by PARP1 inhibitors (PARPi) as a cancer treatment strategy is emerging yet requires suitable predictive biomarkers. To address these issues, we performed immunohistochemical analysis of multiple markers of DNA damage signalling, oxidative stress, DNA repair and cell cycle control pathways during progression of human prostate disease from benign hyperplasia, through intraepithelial neoplasia to CaP, complemented by genetic analyses of TMPRSS2-ERG rearrangement and NQO1, an anti-oxidant factor and p53 protector. The DNA damage checkpoint barrier (γH2AX, pATM, p53) mechanism was activated during CaP tumorigenesis, albeit less and with delayed culmination compared to other cancers, possibly reflecting lower replication stress (slow proliferation despite cases of Rb loss and cyclin D1 overexpression) and progressive loss of ATM activator NKX3.1. Oxidative stress (8-oxoguanine lesions) and NQO1 increased during disease progression. NQO1 genotypes of 390 men did not indicate predisposition to CaP, yet loss of NQO1 in CaP suggested potential progression-opposing tumour suppressor role. TMPRSS2-ERG rearrangement and PTEN loss, events sensitizing to PARPi, occurred frequently along with heterogeneous loss of DNA repair factors 53BP1, JMJD1C and Rev7 (all studied here for the first time in CaP) whose defects may cause resistance to PARPi. Overall, our results reveal an unorthodox DNA damage checkpoint barrier scenario in CaP tumorigenesis, and provide novel insights into oxidative stress and DNA repair, with implications for biomarker guidance of future targeted therapy of CaP.
- MeSH
- PTEN Phosphohydrolase analysis genetics MeSH
- Oncogene Proteins, Fusion analysis genetics MeSH
- Genotype MeSH
- Middle Aged MeSH
- Humans MeSH
- NAD(P)H Dehydrogenase (Quinone) analysis genetics MeSH
- Prostatic Neoplasms genetics metabolism pathology MeSH
- DNA Repair MeSH
- Oxidative Stress * MeSH
- DNA Damage * MeSH
- Disease Progression MeSH
- Prostate metabolism pathology MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: The TMPRSS2-ERG gene fusion is one of the most widely spread chromosomal rearrangements in carcinomas. Since its discovery, a number of studies have examined its diagnostic, prognostic and therapeutic implications for prostate cancer where suitable biomarkers are still lacking. The publication data are inconsistent. The aim of this review was to critically evaluate the current clinical impact of this gene fusion. METHODS: The PubMed online database was used to search relevant reviews and original articles. RESULTS: Although the TMPRSS2-ERG gene fusion appears to be a suitable diagnostic biomarker, the prognostic implications of this gene fusion are still unclear. Several new strategies for therapeutically targeting ETS fusions and their modulators have been identified and are currently being investigated. CONCLUSION: Due to the heterogeneity of prostate cancer, the combination of several biomarkers is necessary to accurately assess the presence of prostate cancer, predict its potential clinical outcome and decide on appropriate therapy (e.g. PARP inhibitors).
- MeSH
- Gene Fusion genetics MeSH
- Oncogene Proteins, Fusion genetics MeSH
- Humans MeSH
- Biomarkers, Tumor MeSH
- Prostatic Neoplasms diagnosis genetics MeSH
- Prognosis MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Fusion of TMPRSS2 with ERG in prostate cells is determined by double-strand DNA breaks induced by androgen signaling and transcription stress. The enzyme topoisomerase 2beta (TOP2B) mediating DNA processing, plays an important role in DNA cleavage. The aim of this study was to analyse expression of AR, TOP2B and ERG in relation to TMPRSS2-ERG gene rearrangement and relevant clinicopathological characteristics in prostate cancer (CaP). Immunohistochemical staining and FISH were used for investigation. ERG expression in prostate cell lesions positively correlated with levels of TMPRSS2-ERG fusion gene (p<0.0001). The most significant co-expression of ERG was found with AR in CaP (p=0.001). Significantly more frequent co-expression of ERG was also revealed with TOP2B (p=0.028). ERG protein expression did not correlate with CaP differentiation status as we found no significant differences in ERG expression for different Gleason categories. We demonstrated a statistically significant positive correlation between the percentage of cells with fusion gene TMPRSS2-ERG in CaP and metastatic potential of tumors (p=0.011). Besides these positive corelations of AR with ERG (p=0.001) and TOP2B with ERG (p=0.028), we also demonstrated a significant co-expression of AR with TOP2B (p=0.007) in CaP. There was a statistically significant increase in the TOP2B H-index in locally advanced CaP in comparison with localized tumors (p=0.046). ERG expression correlates with occurrence of TMPRSS2-ERG fusion and with AR-driven malignant transformation. The results indicate that detection of the TMPRSS2-ERG fusion gene and parallel immunohistochemical examination of AR, TOP2B and ERG has diagnostic significance and may be useful in assessing the biological character of the prostate cancer as well as selecting the best treatment.
- MeSH
- Receptors, Androgen * analysis physiology MeSH
- DNA-Binding Proteins * analysis MeSH
- DNA Topoisomerases, Type II * analysis MeSH
- Gene Fusion * MeSH
- Oncogene Proteins, Fusion * genetics MeSH
- Gene Rearrangement MeSH
- Immunohistochemistry MeSH
- Humans MeSH
- Prostatic Neoplasms MeSH
- Trans-Activators * analysis MeSH
- Transcriptional Regulator ERG MeSH
- Check Tag
- Humans MeSH
- Male MeSH
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
32 l., 40 l. příl. : il., tab. ; 30 cm
Na odpovídajícím prospektivním i retrospektivním souboru pacientů s BPH, CaP a AGA budou testovány níže uvedené hypotézy. Polymorfismus genu pro AR (SNP rs6152) může ovlivňovat nejen výskyt, ale i průběh onemocnění závislých na funkčním AR (BPH, CaP, AGA). Změny exprese sledovaných androgeny regulovaných genů mohou zpřesnit diagnostiku časných fází CaP (PCA3, KLK7/11) nebo definovat pacienty, kteří budou profitovat z radikální léčby (TMPRSS2-ERG). Současná přítomnost alely G (SNP rs6152) a určitého typuAGA může predikovat vyšší riziko výskytu agresivně se chovajících CaP.; The below mentioned hypotheses will be tested using appropriate prospective as well as retrospective sample of patients with BPH, CaP and AGA. AR gene polymorphism (SNP rs6152) can have impact not only on incidence but also on course of androgen receptordependent disorders such as BPH, CaP and AGA. Changes in expression of investigated androgen sensitive genes (PCA3, KLK7/11) could make diagnosis of earlier CaP more precise and/or, in the case TMPRSS2-ERG, define patients who could benefit from radicaltreatment. The existence of G allele in SNP rs6152 together with certain types of AGA could predict higher risk for aggressive (metastazing) CaP.
- MeSH
- Alopecia MeSH
- Androgens MeSH
- Prostatic Hyperplasia MeSH
- Prostatic Neoplasms MeSH
- Polymorphism, Genetic MeSH
- Gene Expression Regulation MeSH
- Conspectus
- Biochemie. Molekulární biologie. Biofyzika
- NML Fields
- andrologie
- biologie
- NML Publication type
- závěrečné zprávy o řešení grantu IGA MZ ČR
