Urinary RNA-based biomarkers for prostate cancer detection (original) (raw)

2017, Clinica Chimica Acta

https://doi.org/10.1016/J.CCA.2017.08.009

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Abstract

Prostate-Specific Membrane Antigen (PSMA), prostatic Massage (PM), expressed prostatic secretions (EPS), Homeobox C6 (HOXC6), Tudor Domain Containing 1 (TDRD1), Homeobox 1 (DLX1), Serine Peptidase Inhibitor Kazal type 1 (SPINK1), Second Chromosome Loss Associated with Prostate-1 (SCHLAP1), Metastases Associated Long Adenocarcinoma Transcript 1 (MALAT1), total extravescicles (TEV), exosome-enriched fraction of vesicles (ERV), expressed prostatic secretions in urine (EPS urine).

Semen miRNAs Contained in Exosomes as Non-Invasive Biomarkers for Prostate Cancer Diagnosis

Scientific Reports

Although it is specific for prostatic tissue, serum prostate-specific antigen (PSA) screening has resulted in an over-diagnosis of prostate cancer (PCa) and many unnecessary biopsies of benign disease due to a well-documented low cancer specificity, thus improvement is required. We profiled the expression level of miRNAs contained in semen exosomes from men with moderately increased PSA levels to assess their usefulness, either alone or in addition to PSA marker, as non-invasive biomarkers, for the early efficient diagnosis and prognosis of PCa. An altered miRNA expression pattern was found by a high throughput profiling analysis in PCa when compared with healthy individuals (HCt) exosomal semen samples. The presence of vasectomy was taken into account for the interpretation of results. Fourteen miRNAs were selected for miRNA validation as PCa biomarkers in a subsequent set of semen samples. In this explorative study, we describe miRNA-based models, which included miRNA expression v...

A Model to Detect Significant Prostate Cancer Integrating Urinary Peptide and Extracellular Vesicle RNA Data

Cancers

There is a clinical need to improve assessment of biopsy-naïve patients for the presence of clinically significant prostate cancer (PCa). In this study, we investigated whether the robust integration of expression data from urinary extracellular vesicle RNA (EV-RNA) with urine proteomic metabolites can accurately predict PCa biopsy outcome. Urine samples collected within the Movember GAP1 Urine Biomarker study (n = 192) were analysed by both mass spectrometry-based urine-proteomics and NanoString gene-expression analysis (167 gene-probes). Cross-validated LASSO penalised regression and Random Forests identified a combination of clinical and urinary biomarkers for predictive modelling of significant disease (Gleason Score (Gs) ≥ 3 + 4). Four predictive models were developed: ‘MassSpec’ (CE-MS proteomics), ‘EV-RNA’, and ‘SoC’ (standard of care) clinical data models, alongside a fully integrated omics-model, deemed ‘ExoSpec’. ExoSpec (incorporating four gene transcripts, six peptides, ...

A Multiplex Assay to Measure RNA Transcripts of Prostate Cancer in Urine

PLoS ONE, 2012

The serum prostate-specific antigen (PSA) test has a high false positive rate. As a single marker, PSA provides limited diagnostic information. A multi-marker test capable of detecting not only tumors but also the potentially lethal ones provides an unmet clinical need. Using the nanoString nCounter gene expression system, a 20-gene multiplex test was developed based on digital gene counting of RNA transcripts in urine as a means to detect prostate cancer. In this test, voided urine is centrifuged to pellet cells and the purified RNA is amplified for hybridization to preselected probesets. Amplification of test cell line RNA appeared not to introduce significant bias, and the counts matched well with gene abundance levels as measured by DNA microarrays. For data analysis, the individual counts were compared to that of b2 microglobulin, a housekeeping gene. Urine samples of 5 pre-operative cases and 2 non-cancer were analyzed. Pathology information was then retrieved. Signals for a majority of the genes were low for non-cancer and low Gleason scores, and 6/6 known prostate cancer markers were positive in the cases. One case of Gleason 4+5 showed, in contrast, strong signals for all cancer-associated markers, including CD24. One non-cancer also showed signals for all 6 cancer markers, and this man might harbor an undiagnosed cancer. This multiplex test assaying a natural waste product can potentially be used for screening, early cancer detection and patient stratification. Diagnostic information is gained from the RNA signatures that are associated with cell types of prostate tumors.

Identification of non-invasive miRNAs biomarkers for prostate cancer by deep sequencing analysis of urinary exosomes

Molecular cancer, 2017

The aim of this study was to identify microRNAs in urinary exosomes that are differently expressed in prostate cancer patients and healthy donors. For this purpose, RNA was extracted from urinary exosomes from 20 prostate cancer patients and 9 healthy males and the microRNAs were analyzed by next generation sequencing. Interestingly, 5 microRNAs - miR-196a-5p, miR-34a-5p, miR-143-3p, miR-501-3p and miR-92a-1-5p - were significantly downregulated in exosomes from prostate cancer patients. Furthermore, RT-qPCR analysis of an independent cohort of 28 prostate cancer patients and 19 healthy males confirmed that miR-196a-5p and miR-501-3p were downregulated in prostate cancer samples. These results suggest that specific microRNAs in urinary exosomes might serve as non-invasive biomarkers for prostate cancer. In particular, miR-196a-5p and miR-501-3p are promising biomarkers that need to be further studied in large patient cohorts.

Affinity Captured Urinary Extracellular Vesicles Provide mRNA and miRNA Biomarkers for Improved Accuracy of Prostate Cancer Detection: A Pilot Study

International Journal of Molecular Sciences, 2020

Serum prostate-specific antigen (sPSA) testing has helped to increase early detection of and decrease mortality from prostate cancer. However, since sPSA lacks specificity, an invasive prostate tissue biopsy is required to confirm cancer diagnosis. Using urinary extracellular vesicles (EVs) as a minimally invasive biomarker source, our goal was to develop a biomarker panel able to distinguish prostate cancer from benign conditions with high accuracy. We enrolled 56 patients in our study, 28 negative and 28 positive for cancer based on tissue biopsy results. Using our Vn96 peptide affinity method, we isolated EVs from post-digital rectal exam urines and used quantitative polymerase chain reaction to measure several mRNA and miRNA targets. We identified a panel of seven mRNA biomarkers whose expression ratio discriminated non-cancer from cancer with an area under the curve (AUC) of 0.825, sensitivity of 75% and specificity of 84%. We also identified two miRNAs whose combined score yie...

Biomarkers in Prostate Cancer Diagnosis: From Current Knowledge to the Role of Metabolomics and Exosomes

International Journal of Molecular Sciences

Early detection of prostate cancer (PC) is largely carried out using assessment of prostate-specific antigen (PSA) level; yet it cannot reliably discriminate between benign pathologies and clinically significant forms of PC. To overcome the current limitations of PSA, new urinary and serum biomarkers have been developed in recent years. Although several biomarkers have been explored in various scenarios and patient settings, to date, specific guidelines with a high level of evidence on the use of these markers are lacking. Recent advances in metabolomic, genomics, and proteomics have made new potential biomarkers available. A number of studies focused on the characterization of the specific PC metabolic phenotype using different experimental approaches has been recently reported; yet, to date, research on metabolomic application for PC has focused on a small group of metabolites that have been known to be related to the prostate gland. Exosomes are extracellular vesicles that are se...

Pre-diagnosis urine exosomal RNA (ExoDx EPI score) is associated with post-prostatectomy pathology outcome

World Journal of Urology, 2022

Purpose ExoDx Prostate IntelliScore (EPI) is a non-invasive urine exosome RNA-based test for risk assessment of high-grade prostate cancer. We evaluated the association of pre-biopsy test results with post-radical prostatectomy (RP) outcomes to understand the potential utility of EPI to inform invasive treatment vs active surveillance (AS) decisions. Methods Urine samples were collected from 2066 men scheduled for initial biopsy with PSA between 2 and 10 ng/mL, no history of prostate cancer, and ≥ 50 years across multiple clinical studies. 310 men proceeded to RP, of which 111 patients had Gleason group grade 1 (GG1) at biopsy and would have been potential candidates for AS. We compared pre-biopsy urine scores with ERSPC and PCPT multivariate risk calculator scores for men with GG1 at biopsy to post-RP pathology. Results Urine EPI scores were significantly lower in men with GG1 at biopsy than in men with > GG1 (p = 0.04), while there were no differences in multivariate risk score...

Recent progress in urinary proteome analysis for prostate cancer diagnosis and management

Expert Review of Molecular Diagnostics, 2015

Bijnsdorp, I. V., et al. (2013). "Exosomal ITGA3 interferes with non-cancerous prostate cell functions and is increased in urine exosomes of metastatic prostate cancer patients." Journal of extracellular vesicles 2. BACKGROUND: Cancer cells are able to change the protein expression and behavior of non-cancerous surrounding cells. Exosomes, secreted by prostate cancer (PCa) cells, may have a functional role in cancer metastasis and present a promising source for protein biomarkers. The aim of the present study was to identify which proteins in exosomes can influence non-cancerous cells, and to determine whether we can use urine exosomal proteins to identify high-risk PCa patients. METHOD: Exosomes were isolated by ultracentrifugation. Migration and invasion were studied by the transwell (invasion) assay. Proteomics was performed by LC-MS/MS and identified proteins were validated by Western blotting. Cellular uptake of fluorescent labeled PKH67-exosomes was measured by FACS. RESULTS: Based on comparative protein profiling by mass spectrometry-based proteomics of LNCaP-and PC3-exosomes, we selected ITGA3 and ITGB1, involved in migration/invasion, for further analyses. Inhibition of exosomal ITGA3 reduced the migration and invasion of non-cancerous prostate epithelial cells (prEC) almost completely. Cellular uptake of exosomes by prEC was higher with PC3-exosomes compared to LNCaP exosomes. Finally, ITGA3 and ITGB1 were more abundant in urine exosomes of metastatic patients (p<0.05), compared to benign prostate hyperplasia or PCa. CONCLUSION: These data indicate exosomal ITGA3 and ITGB1 may play a role in manipulating non-cancerous surrounding cells and that measurement of ITGA3 and ITGB1 in urine exosomes has the potential to identify patients with metastatic PCa in a non-invasive manner. Bilgin Dogru, E., et al. (2014). "EMMPRIN and ADAM12 in prostate cancer: preliminary results of a prospective study." Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 35(11): 11647-11653. Extracellular metalloproteinase inducer (EMMPRIN) and a disintegrin and metalloproteinase (ADAM12) play a major role in cancer invasion and metastasis owing to the fact that they are directly related to the cell microenvironment and extracellular matrix (ECM) degradation. The aim of this study was to search for an answer to the question "whether the determination of EMMPRIN and ADAM12 values especially in urine may be helpful for the early diagnosis of prostate cancer without employing invasive methods" and also to check whether they may be useful for the determination of the patients with high metastasis risk. Peripheral blood and urine from 66 prostate cancer patients (40 local, 20 locally advanced, 6 metastatic) and 14 healthy controls were evaluated by enzyme-linked immunosorbent assay (ELISA) method. Serum EMMPRIN and ADAM12 values of the patients were seen to be statistically higher than the serum EMMPRIN and ADAM12 values of the healthy controls (p=0.01 and p=0.001, respectively). The urine ADAM12 levels were significantly higher in patients (p=0.013). No significant relationships were found between urine EMMPRIN values of the patients and the healthy controls (p>0.05). Positive correlation between urine EMMPRIN-urine ADAM12 tests was found in total patients group (r=0.683, p=0.001). Our preliminary results revealed that serum EMMPRIN and ADAM12 values and urine ADAM12 values may be useful markers in prostate cancer therapy. Due to the high correlation between these two tests, we are of the opinion that the use of urine ADAM12 in clinic may be sufficient and favorable together with prostatespecific antigen (PSA) for treatment. Cao, D.-L., et al. (2011).

A Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer at Initial Biopsy

JAMA oncology, 2016

Overdiagnosis and overtreatment of indolent prostate cancer (PCA) is a serious health issue in most developed countries. There is an unmet clinical need for noninvasive, easy to administer, diagnostic assays to help assess whether a prostate biopsy is warranted. To determine the performance of a novel urine exosome gene expression assay (the ExoDx Prostate IntelliScore urine exosome assay) plus standard of care (SOC) (ie, prostate-specific antigen [PSA] level, age, race, and family history) vs SOC alone for discriminating between Gleason score (GS)7 and GS6 and benign disease on initial biopsy. In training, using reverse-transcriptase polymerase chain reaction (PCR), we compared the urine exosome gene expression assay with biopsy outcomes in 499 patients with prostate-specific antigen (PSA) levels of 2 to20 ng/mL. The derived prognostic score was then validated in 1064 patients from 22 community practice and academic urology clinic sites in the United States. Eligible participants i...

A preliminary study of micro-RNAs as minimally invasive biomarkers for the diagnosis of prostate cancer patients

Journal of Experimental & Clinical Cancer Research, 2021

Background A prostate cancer diagnosis is based on biopsy sampling that is an invasive, expensive procedure, and doesn’t accurately represent multifocal disease. Methods To establish a model using plasma miRs to distinguish Prostate cancer patients from non-cancer controls, we enrolled 600 patients histologically diagnosed as having or not prostate cancer at biopsy. Two hundred ninety patients were eligible for the analysis. Samples were randomly divided into discovery and validation cohorts. Results NGS-miR-expression profiling revealed a miRs signature able to distinguish prostate cancer from non-cancer plasma samples. Of 51 miRs selected in the discovery cohort, we successfully validated 5 miRs (4732-3p, 98-5p, let-7a-5p, 26b-5p, and 21-5p) deregulated in prostate cancer samples compared to controls (p ≤ 0.05). Multivariate and ROC analyses show miR-26b-5p as a strong predictor of PCa, with an AUC of 0.89 (CI = 0.83–0.95;p

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Expression of Small Noncoding RNAs in Urinary Exosomes Classifies Prostate Cancer into Indolent and Aggressive Disease

Journal of Urology, 2020

This is the first report of the development and performance of a platform that interrogates small noncoding RNAs (sncRNA) isolated from urinary exosomes. The SentinelÔ PCa Test classifies patients with prostate cancer from subjects with no evidence of prostate cancer, the miR Sentinel CS Test stratifies patients with prostate cancer between those with low risk prostate cancer (Grade Group 1) from those with intermediate and high risk disease (Grade Group 2-5), and the miR Sentinel HG Test stratifies patients with prostate cancer between those with low and favorable intermediate risk prostate cancer (Grade Group 1 or 2) and those with high risk (Grade Group 3-5) disease. Materials and Methods: sncRNAs were extracted from urinary exosomes of 235 participants and interrogated on miR 4.0 microarrays. Using proprietary selection and classification algorithms, informative sncRNAs were selected to customize an interrogation OpenArrayÔ platform that forms the basis of the tests. The tests were validated using a case-control sample of 1,436 subjects. The performance of the miR Sentinel PCa Test demonstrated a sensitivity of 94% and specificity of 92%. The Sentinel CS Test demonstrated a sensitivity of 93% and specificity of 90% for prediction of the presence of Grade Group 2 or greater cancer, and the Sentinel HG Test demonstrated a sensitivity of 94% and specificity of 96% for the prediction of the presence of Grade Group 3 or greater cancer. The Sentinel PCa, CS and HG Tests demonstrated high levels of sensitivity and specificity, highlighting the utility of interrogation of urinary exosomal sncRNAs for noninvasively diagnosing and classifying prostate cancer with high precision.

Urinary extracellular vesicles miRNA—A new era of prostate cancer biomarkers

Frontiers in Genetics

Prostate cancer is the second most common male cancer worldwide showing the highest rates of incidence in Western Europe. Although the measurement of serum prostate-specific antigen levels is the current gold standard in PCa diagnosis, PSA-based screening is not considered a reliable diagnosis and prognosis tool due to its lower sensitivity and poor predictive score which lead to a 22%–43% overdiagnosis, unnecessary biopsies, and over-treatment. These major limitations along with the heterogeneous nature of the disease have made PCa a very unappreciative subject for diagnostics, resulting in poor patient management; thus, it urges to identify and validate new reliable PCa biomarkers that can provide accurate information in regard to disease diagnosis and prognosis. Researchers have explored the analysis of microRNAs (miRNAs), messenger RNAs (mRNAs), small proteins, genomic rearrangements, and gene expression in body fluids and non-solid tissues in search of lesser invasive yet effic...

Urine Exosomes for Non-Invasive Assessment of Gene Expression and Mutations of Prostate Cancer

PloS one, 2016

The analysis of exosome/microvesicle (extracellular vesicles (EVs)) and the RNA packaged within them (exoRNA) has the potential to provide a non-invasive platform to detect and monitor disease related gene expression potentially in lieu of more invasive procedures such as biopsy. However, few studies have tested the diagnostic potential of EV analysis in humans. The ability of EV analysis to accurately reflect prostate tissue mRNA expression was examined by comparing urinary EV TMPRSS2:ERG exoRNA from pre-radical prostatectomy (RP) patients versus corresponding RP tissue in 21 patients. To examine the differential expression of TMPRSS2:ERG across patient groups a random urine sample was taken without prostate massage from a cohort of 207 men including prostate biopsy negative (Bx Neg, n = 39), prostate biopsy positive (Bx Pos, n = 47), post-radical prostatectomy (post-RP, n = 37), un-biopsied healthy age-matched men (No Bx, n = 44), and young male controls (Cont, n = 40). The use of...

Urinary-exosomal miR-2909: A novel pathognomonic trait of prostate cancer severity

The global occurrence of prostate cancer with a range of patient outcome has prompted various investigators to explore novel molecular biomarkers that can precisely detect and track this type of cancer severity. Several studies suggest that micro-RNAs have emerged to act as a new largely unexplored class of biomarkers because of their inherent stability, resilience and recruitment into exosomes present in various human body fluids. With this study, we aim to reveal the nature of urinary-exosomal miR-2909 & miR-615-3p recruitment in patients suffering from either prostate cancer (n = 90) or bladder cancer (n = 60) as compared to that in either prostate disease-control subjects having benign prostate hyperplasia (n = 10) or healthy subjects (n = 50). Unlike miR-615-3p, the urinary-exosomal miR-2909 recruitment was not only observed conspicuously in subjects having prostate cancer in comparison to bladder cancer but also the extent of urinary exosomal miR-2909 recruitment showed characteristic variation as a function of prostate cancer aggressiveness as compared to that of either urinary-exosomal miR-615-3p level or existing widely recognised serum prostate specifics antigen (PSA) biomarker of this cancer. In summary, we propose that the extent of urinary exosomal miR-2909 recruitment may provide a potential non-invasive candidate diagnostic marker for the detection of prostate cancer and its aggressiveness.

Long Non-Coding RNAs in Plasma and Urine as Potential Biomarkers in Prostate Cancer

Timisoara Medical Journal, 2021

  1. Introduction: Prostate cancer is the second leading cause of cancer-related death in men in developed countries. Due to the existing biomarkers' limitations, there is a stringent need to develop novel, better non-invasive markers for prostate cancer diagnostic and monitoring. (2) Material and methods: We assessed, by real-time PCR, the expression level of 84 long non-coding RNA (lncRNA) in plasma and the exosomes isolated from prostate cancer patients' plasma and urine. (3) Results: Only a few lncRNAs were detected in high abundance (Ct between 25 and 30 cycles) across all sample types, the vast majority showing relatively modest levels (Ct > 30 cycles). As expected, plasma and plasma exosomes contain far more lncRNA species than urine, irrespective of whether they originate from patients or controls. We identified two statistically significant dysregulated lncRNAs in prostate cancer samples vs. controls: RBM5-AS1, 2.89 times downregulated in plasma (p = 0.036), and SNHG16, 13.69 times upregulated (p = 0.029) in urine exosomes. (4) Conclusions: These preliminary data need further validation in additional independent, more extensive studies before they can be considered as biomarkers for prostate cancer.

Distinct prostate cancer-related mRNA cargo in extracellular vesicle subsets from prostate cell lines

BMC Cancer, 2017

Background: Multiple types of extracellular vesicles (EVs), including microvesicles (MVs) and exosomes (EXOs), are released by all cells constituting part of the cellular EV secretome. The bioactive cargo of EVs can be shuffled between cells and consists of lipids, metabolites, proteins, and nucleic acids, including multiple RNA species from non-coding RNAs to messenger RNAs (mRNAs). In this study, we hypothesized that the mRNA cargo of EVs could differ based on the EV cellular origin and subpopulation analyzed. Methods: We isolated MVs and EXOs from PC-3 and LNCaP prostate cancer cells by differential centrifugation and compared them to EVs derived from the benign PNT2 prostate cells. The relative mRNA levels of 84 prostate cancerrelated genes were investigated and validated using quantitative reverse transcription PCR arrays. Results: Based on the mRNA abundance, MVs rather than EXOs were enriched in the analyzed transcripts, providing a snapshot of the tumor transcriptome. LNCaP MVs specifically contained significantly increased mRNA levels of NK3 Homeobox 1 (NKX3-1), transmembrane protease serine 2 (TMPRSS2), and tumor protein 53 (TP53) genes, whereas PC-3 MVs carried increased mRNA levels of several genes including, caveolin-2 (CAV2), glutathione S-transferase pi 1 (GSTP1), pescadillo ribosomal biogenesis factor 1 (PES1), calmodulin regulated spectrin associated protein 1 (CAMSAP1), zincfinger protein 185 (ZNF185), and others compared to PNT2 MVs. Additionally, ETS variant 1 (ETV1) and fatty acid synthase (FASN) mRNAs identified in LNCaP-and PC-3-derived MVs highly correlated with prostate cancer progression.

Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer

British journal of cancer, 2009

Herein, we describe a novel approach in the search for prostate cancer biomarkers, which relies on the transcriptome within tumour exosomes. As a proof-of-concept, we show the presence of two known prostate cancer biomarkers, PCA-3 and TMPRSS2:ERG the in exosomes isolated from urine of patients, showing the potential for diagnosis and monitoring cancer patients status.

Proteomic Profiling of Exosomes Leads to the Identification of Novel Biomarkers for Prostate Cancer

PLoS ONE, 2013

Background: Current markers for prostate cancer, such as PSA lack specificity. Therefore, novel biomarkers are needed. Unfortunately, the complexity of body fluids often hampers biomarker discovery. An attractive alternative approach is the isolation of small vesicles, i.e. exosomes, ,100 nm, which contain proteins that are specific to the tissue from which they are derived and therefore can be considered as treasure chests for disease-specific biomarker discovery.

Circulating mRNA signature as a marker for high-risk prostate cancer

Carcinogenesis, 2019

Prostate cancer (PCa) is the second most common cancer in men. The indolent course of the disease makes the treatment choice a challenge for physicians and patients. In this study, a minimally invasive method was used to evaluate the potential of molecular markers in identifying patients with aggressive disease. Cell-free plasma samples from 60 PCa patients collected before radical prostatectomy were used to evaluate the levels of expression of eight genes (AMACR, BCL2, NKX3-1, GOLM1, OR51E2, PCA3, SIM2 and TRPM8) by quantitative real-time PCR. Overexpression of AMACR, GOLM1, TRPM8 and NKX3-1 genes was significantly associated with aggressive disease characteristics, including extracapsular extension, tumor stage and vesicular seminal invasion. A trio of genes (GOLM1, NKX3-1 and TRPM8) was able to identify high-risk PCa cases (85% of sensitivity and 58% of specificity), yielding a better overall performance compared with the biopsy Gleason score and prostate-specific antigen, routin...

Diagnosis of Prostate Cancer through the Multi-Ligand Binding of Prostate-Derived Extracellular Vesicles and miRNA Analysis

Life

Background: The development of new non-invasive markers for prostate cancer (PC) diagnosis, prognosis, and management is an important issue that needs to be addressed to decrease PC mortality. Small extracellular vesicles (SEVs) secreted by prostate gland or prostate cancer cells into the plasma are considered next-generation diagnostic tools because their chemical composition might reflect the PC development. The population of plasma vesicles is extremely heterogeneous. The study aimed to explore a new approach for prostate-derived SEV isolation followed by vesicular miRNA analysis. Methods: We used superparamagnetic particles functionalized by five types of DNA-aptamers binding the surface markers of prostate cells. Specificity of binding was assayed by AuNP-aptasensor. Prostate-derived SEVs were isolated from the plasma of 36 PC patients and 18 healthy donors and used for the assessment of twelve PC-associated miRNAs. The amplification ratio (amp-ratio) value was obtained for all...

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Beyond PSA: The Role of Prostate Health Index (phi)

International Journal of Molecular Sciences

Background: Widespread use of prostate specific antigen (PSA) in screening procedures allowed early identification of an increasing number of prostate cancers (PCas), mainly including indolent cancer. Availability of different therapeutic strategies which have a very different impact on the patient’s quality of life suggested a strong need for tools able to identify clinically significant cancer at diagnosis. Multi-parametric magnetic resonance showed very good performance in pre-biopsy diagnosis. However, it is an expensive tool and requires an experienced radiologist. In this context, a simple blood-based test is worth investigating. In this context, researchers focused their attention on the development of a laboratory test able to minimize overdiagnosis without losing the identification of aggressive tumors. Results: Recent literature data on PCa biomarkers revealed a clear tendency towards the use of panels of biomarkers or a combination of biomarkers and clinical variables. Ph...

Long Non-Coding RNA Regulation of Epigenetics in Vascular Cells

Non-Coding RNA

The vascular endothelium comprises the interface between the circulation and the vessel wall and, as such, is under the dynamic regulation of vascular signalling, nutrients, and hypoxia. Understanding the molecular drivers behind endothelial cell (EC) and vascular smooth muscle cell (VSMC) function and dysfunction remains a pivotal task for further clinical progress in tackling vascular disease. A newly emerging era in vascular biology with landmark deep sequencing approaches has provided us with the means to profile diverse layers of transcriptional regulation at a single cell, chromatin, and epigenetic level. This review describes the roles of major vascular long non-coding RNA (lncRNAs) in the epigenetic regulation of EC and VSMC function and discusses the recent progress in their discovery, detection, and functional characterisation. We summarise new findings regarding lncRNA-mediated epigenetic mechanisms—often regulated by hypoxia—within the vascular endothelium and smooth mus...

Searching for the Novel Specific Predictors of Prostate Cancer in Urine: The Analysis of 84 miRNA Expression

2018

The aim of this study was to investigate miRNA profiles of clarified urine supernatant and combined urine vesicle fractions of healthy donors and patients with benign prostatic hyperplasia and prostate cancer (PCa). The comparative analysis of miRNA expression was conducted with a custom miRCURY LNA miRNA qPCR panel. Significant combinations of miRNA pairs were selected by the RandomForest-based feature selection algorithm Boruta; the difference of the medians between the groups and a 95% confidence interval was built using the bootstrap approach. The Asymptotic Wilcoxon-Mann-Whitney Test was performed for miRNA combinations to compare different groups of donors. Benjamini-Hochberg correction was used to adjust the statistical significance for multiple comparisons. The most diagnostically significant miRNAs pairs were miR-107-miR-26b.5p and miR-375.3p-miR-26b.5p in the urine supernatant fraction that discriminated the group of healthy patients and PCa patients, as well as miR-31.5p-...

Noncoding RNAs in Extracellular Fluids as Cancer Biomarkers: The New Frontier of Liquid Biopsies

Cancers, 2019

The last two decades of cancer research have been devoted in two directions: (1) understanding the mechanism of carcinogenesis for an effective treatment, and (2) improving cancer prevention and screening for early detection of the disease. This last aspect has been developed, especially for certain types of cancers, thanks also to the introduction of new concepts such as liquid biopsies and precision medicine. In this context, there is a growing interest in the application of alternative and noninvasive methodologies to search for cancer biomarkers. The new frontiers of the research lead to a search for RNA molecules circulating in body fluids. Searching for biomarkers in extracellular body fluids represents a better option for patients because they are easier to access, less painful, and potentially more economical. Moreover, the possibility for these types of samples to be taken repeatedly, allows a better monitoring of the disease progression or treatment efficacy for a better i...

Artificial Intelligence for Clinical Diagnosis and Treatment of Prostate Cancer

Cancers

As medical science and technology progress towards the era of “big data”, a multi-dimensional dataset pertaining to medical diagnosis and treatment is becoming accessible for mathematical modelling. However, these datasets are frequently inconsistent, noisy, and often characterized by a significant degree of redundancy. Thus, extensive data processing is widely advised to clean the dataset before feeding it into the mathematical model. In this context, Artificial intelligence (AI) techniques, including machine learning (ML) and deep learning (DL) algorithms based on artificial neural networks (ANNs) and their types, are being used to produce a precise and cross-sectional illustration of clinical data. For prostate cancer patients, datasets derived from the prostate-specific antigen (PSA), MRI-guided biopsies, genetic biomarkers, and the Gleason grading are primarily used for diagnosis, risk stratification, and patient monitoring. However, recording diagnoses and further stratifying ...

Approaches to urinary detection of prostate cancer

Prostate Cancer and Prostatic Diseases, 2019

Background: Prostate cancer is the most common cancer in American men that ranges from low risk states amenable to active surveillance to high risk states that can be lethal especially if untreated. There is a critical need to develop relatively non-invasive and clinically useful methods for screening, detection, prognosis, disease monitoring, and prediction of treatment efficacy. In this review, we focus on important advances as well as future efforts needed to drive clinical innovation in this area of urine biomarker research for prostate cancer detection and prognostication. Methods: We provide a review of current literature on urinary biomarkers for prostate cancer. We evaluate the strengths and limitations of a variety of approaches that vary in sampling strategies and targets measured; discuss reported urine tests for prostate cancer with respect to their technical, analytical, and clinical parameters; and provide our perspectives on critical considerations in approaches to developing a urine-based test for prostate cancer. Results: There has been an extensive history of exploring urine as a source of biomarkers for prostate cancer that has resulted in a variety of urine tests that are in current clinical use. Importantly, at least three tests have demonstrated high sensitivity (~90%) and negative predictive value (~95%) for clinically significant tumors; however, there has not been widespread adoption of these tests. Conclusions: Conceptual and methodological advances in the field will help to drive the development of novel urinary tests that in turn may lead to a shift in the clinical paradigm for prostate cancer diagnosis and management.

Elucidation of Epigenetic Landscape in Coronary Artery Disease: A Review on Basic Concept to Personalized Medicine

Epigenetics Insights, 2021

Despite extensive clinical research and management protocols applied in the field of coronary artery diseases (CAD), it still holds the number 1 position in mortality worldwide. This indicates that we need to work on precision medicine to discover the diagnostic, therapeutic, and prognostic targets to improve the outcome of CAD. In precision medicine, epigenetic changes play a vital role in disease onset and progression. Epigenetics is the study of heritable changes that do not affect the alterations of DNA sequence in the genome. It comprises various covalent modifications that occur in DNA or histone proteins affecting the spatial arrangement of the DNA and histones. These multiple modifications include DNA/histone methylation, acetylation, phosphorylation, and SUMOylation. Besides these covalent modifications, non-coding RNAs—viz. miRNA, lncRNA, and circRNA are also involved in epigenetics. Smoking, alcohol, diet, environmental pollutants, obesity, and lifestyle are some of the p...

The Emerging Roles of Long Non-Coding RNAs in Intellectual Disability and Related Neurodevelopmental Disorders

International Journal of Molecular Sciences

In the human brain, long non-coding RNAs (lncRNAs) are widely expressed in an exquisitely temporally and spatially regulated manner, thus suggesting their contribution to normal brain development and their probable involvement in the molecular pathology of neurodevelopmental disorders (NDD). Bypassing the classic protein-centric conception of disease mechanisms, some studies have been conducted to identify and characterize the putative roles of non-coding sequences in the genetic pathogenesis and diagnosis of complex diseases. However, their involvement in NDD, and more specifically in intellectual disability (ID), is still poorly documented and only a few genomic alterations affecting the lncRNAs function and/or expression have been causally linked to the disease endophenotype. Considering that a significant fraction of patients still lacks a genetic or molecular explanation, we expect that a deeper investigation of the non-coding genome will unravel novel pathogenic mechanisms, op...

The emerging landscape of tumor marker panels for the identification of aggressive prostate cancer: the perspective through bibliometric analysis of an Italian translational working group in uro-oncology

Minerva Urology and Nephrology, 2021

Molecular heterogeneity and availability of different therapeutic strategies are relevant clinical features of prostate cancer. On this basis, there is an urgent need to identify prognostic and predictive biomarkers for an individualized therapeutic approach. In this context, researchers focused their attention on biomarkers able to discriminate potential life-threatening from organ-confined disease. Such biomarker could provide aid in clinical decision making, helping to choose the treatment which ensures the best results in terms of patient survival and quality of life. To address this need, many new laboratory tests have been proposed, with a clear tendency to use panels of combined biomarkers. In this review we evaluate current data on the application in clinical practice of the most promising laboratory tests: Phi, 4K score and Stockholm 3 as circulating biomarkers, Mi-prostate score, Exo DX Prostate and Select MD-X as urinary biomarkers, Confirm MDx, Oncotype Dx, Prolaris and Decipher as tissue biomarkers. In particular, the ability of these tests in the identification of clinically significant PCa and their potential use for precision medicine have been explored in this review.