Prospective Multicentre Evaluation of PCA3 and TMPRSS2-ERG Gene Fusions as Diagnostic and Prognostic Urinary Biomarkers for Prostate Cancer

Leyten, G.H.J.M.; Hessels, Daphne; Jannink, Sander A.; Smit, Frank; Jong, Hans de; Cornel, Erik B.; Reijke, Theo M. de; Vergunst, H.; Kil, Paul; Knipscheer, Ben C.; Oort, Inge M. van; Mulders, Peter F.A.; Kaa, Christina A. Hulsbergen‐van de; Schalken, Jack A.

doi:10.1016/j.eururo.2012.11.014

Cited by 314 publications

(261 citation statements)

References 24 publications

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“…For example, in EVs from a prostate tumour cell line, RNA transcripts of the prostate cancer-specific fusion gene TMPRSS2:ERG were detected (Jansen et al 2009). These transcripts, along with mRNA for GOLPH2, SPINK1 and prostate cancer antigen 3, were also found in EVs isolated from the urine of prostate cancer patients (Laxman et al 2008, Nilsson et al 2009, Leyten et al 2012. In semen, cell-free mRNA and miRNA were found both in association with EVs and membrane-free protein complexes (Li et al 2012).…”

Section: The Molecular Composition Of Prostasomesmentioning

confidence: 90%

Prostasomes: extracellular vesicles from the prostate

Aalberts¹,

Stout²,

Stoorvogel³

2014

Reproduction

171

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The term 'prostasomes' is generally used to classify the extracellular vesicles (EVs) released into prostatic fluid by prostate epithelial cells. However, other epithelia within the male reproductive tract also release EVs that mix with 'true' prostasomes during semen emission or ejaculation. Prostasomes have been proposed to regulate the timing of sperm cell capacitation and induction of the acrosome reaction, as well as to stimulate sperm motility where all three are prerequisite processes for spermatozoa to attain fertilising capacity. Other proposed functions of prostasomes include interfering with the destruction of spermatozoa by immune cells within the female reproductive tract. On the other hand, it is unclear whether the distinct presumed functions are performed collectively by a single type of prostasome or by separate distinct sub-populations of EVs. Moreover, the exact molecular mechanisms through which prostasomes exert their functions have not been fully resolved. Besides their physiological functions, prostasomes produced by prostate tumour cells have been suggested to support prostate cancer spread development, and prostasomes in peripheral blood plasma may prove to be valuable biomarkers for prostate cancer.

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Section: The Molecular Composition Of Prostasomesmentioning

confidence: 90%

Prostasomes: extracellular vesicles from the prostate

Aalberts¹,

Stout²,

Stoorvogel³

2014

Reproduction

171

150

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“…CaP, in accordance with previous reports 365 . This preliminary investigation helps to build on current CaP biomarker research literature.…”

Section: Discussionsupporting

confidence: 82%

“…PCA3, a long non-coding RNA, collected in the first void of urine following a vigorous DRE or prostatic massage, has been examined over the past 20 years 362 , with studies reporting to improve detection in men undergoing repeat biopsy 363 , but its role clinically remains uncertain. Modifications of PCA3 364 , as well as a combination with TMPRSS2-ERG fusion gene have been described to improve detection 365 but have not been accepted as a useful addition in routine patient testing 366 . Other approaches utilizing exosomes, proteomics and metabolomics have the potential to improve early diagnosis of localized disease 20,21,367 .…”

Section: Introductionmentioning

confidence: 99%

Multiple markers for the non-invasive diagnosis and characterisation of prostate cancer

Roberts¹

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The early detection of prostate cancer (CaP), the most common internal cancer in men, is limited by an absence of biomarkers that accurately reflect clinically significant disease.Currently, the prostate cancer antigen 3 (PCA3) test in combination with TMPRSS2-ERG fusion gene detection in urine obtained following rectal prostatic massage represent arguably the best standalone biomarkers for CaP but are not widely used in comparison with serum prostate specific antigen (PSA). Limitations in CaP diagnosis and characterisation may be overcome by use of naturally-produced, prostate-specific biofluids, such as ejaculate and post-ejaculate urethral washings (PEUW). Ejaculate is known to contain prostatic cells and relevant molecules in the non-cellular component, while PEUW may contain these as well as biomarkers reflective of systemic changes due to or causing CaP.The overall aim of this thesis was to use molecular and metabolomic nuclear magnetic resonance (NMR)-based detection methods to study prostatic fluid derived from ejaculate and PEUW to improve CaP diagnosis. Specifically, this thesis sought to optimise ejaculate sample processing for metabolomics studies and evaluate the diagnostic performance of mRNA, microRNA and metabolomic markers in ejaculate to complement serum PSA in detecting clinically significant CaP. Furthermore, this thesis investigated the feasibility and performance of PEUW-based mRNA and metabolomic biomarker performance attributable to the presence of ejaculate in urine to reflect local prostatic and systemic alterations in order to more accurately detect clinically significant CaP. Dependent clinical variables considered were absolute (positive/negative) and clinically significant (present/absent) CaP as well as risk groups (low, intermediate, high) according to the D'Amico criteria.Using a NMR-based metabolomics enzyme kinetics study design, the addition of tartrate and cooling of ejaculate samples improved the stability of choline and phosphorylcholine concentrations. Sample collection into a sterile urine jar containing 5 mM (on-site) or 10 mM (off-site) tartrate in 20 ml PBS solution cooled to 277 K and cooled during transport until processing would result in at most a 2-3% change in choline and phosphorylcholine to facilitate sample collection off-site without significant effect on choline-based metabolites.Following prostatic cell RNA isolation, amplification and qPCR for β2-microglobulin (β2M), PSA, PCA3 and Hepsin in ejaculate, adequate RNA for all assays was obtained for 66 patients and determined that a Hepsin:PCA3 ratio in ejaculate together with serum PSA best predicted absolute CaP (AUC= 0.724 vs 0.676) and csCaP (AUC= 0.701 vs 0.680).iii Matched mRNA and microRNA expression was possible for a subgroup of patients (n=20) Lipids/lipoproteins dominated spectra of high grade samples. Overall CaP prediction using metabolites described in previous studies was not validated. However, findings suggest that incorporation of in vitro NMR-based metabolomics may translate to in v...

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“…To our knowledge, changes in mRNA content of EVs isolated from blood of PCa patients have not yet been reported; however, several studies have examined mRNA in EVs isolated from urine. As discussed above, transcripts for TMPRSS2:ERG, PCA3, GOLPH2, and SPINK1 have all been detected in the urine of PCa patients with some predictive value for PCa (20,22,23,67). In most of these studies, it was not clear whether these transcripts were associated with cells, apoptotic bodies, or EVs.…”

Section: Prostasome-associated Mrna and Ncrna Pca Markersmentioning

confidence: 98%