PCA3

Gene Summary

Gene:PCA3; prostate cancer associated 3
Aliases: DD3, PCAT3, NCRNA00019, PRUNE2-AS1
Location:9q21.2
Summary:This gene produces a spliced, long non-coding RNA that is highly overexpressed in most types of prostate cancer cells and is used as a specific biomarker for this type of cancer. This gene is embedded in an intronic region of the prune2 gene on the opposite DNA strand. The transcript regulates prune2 levels through formation of a double-stranded RNA that undergoes adenosine deaminase acting on RNA-dependent adenosine-to-inosine RNA editing. In prostate cancer derived cells, overexpression of PCA induced downregulation of prune2, leading to decreased cell proliferation. Conversely, silencing in prostate cancer cells resulted in increased proliferation. Regulation of this gene appears to be sensitive to androgen-receptor activation, a molecular signature of prostate cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2017]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Sensitivity and Specificity
  • Neoplasm Grading
  • Adenocarcinoma
  • Oncogene Fusion Proteins
  • Gene Expression
  • Tumor Burden
  • Cancer Gene Expression Regulation
  • Androgen Receptors
  • Unnecessary Procedures
  • Tissue Kallikreins
  • Long Noncoding RNA
  • Prostatic Hyperplasia
  • RTPCR
  • Neoplasm Proteins
  • Carrier Proteins
  • Messenger RNA
  • Research Design
  • Gene Expression Profiling
  • Staging
  • Case-Control Studies
  • Testosterone
  • ROC Curve
  • Tumor Antigens
  • Risk Assessment
  • Prostatectomy
  • Prostate-Specific Antigen
  • Promoter Regions
  • Chromosome 9
  • Biomarkers, Tumor
  • Biopsy
  • Reference Standards
  • Prostate Cancer
  • Genetic Predisposition
  • Cancer Screening
  • MicroRNAs
  • Urinalysis
  • Tumor Suppressor Proteins
  • Telomerase
  • Prostate
  • RT-PCR
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PCA3 (cancer-related)

Mao Z, Ji A, Yang K, et al.
Diagnostic performance of PCA3 and hK2 in combination with serum PSA for prostate cancer.
Medicine (Baltimore). 2018; 97(42):e12806 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: The prostate cancer gene 3 (PCA3), human kallikrein 2, and miRNA-141 are promising prostate cancer (Pca) specific biomarkers. Our aim was to evaluate the detection of PCA3, human glandular kallikrein 2 (hk2), and miRNA-141 mRNA in peripheral blood of patients received prostate biopsy. What's more, we want to detect the value of combination of PSA (prostate specific antigen) in the early diagnosis of PCa.
MATERIALS AND METHODS: Hundred patients were divided into 2 groups according to the results of pathologic diagnosis. Quantitative real-time PCR (qRT-PCR) was used to evaluate the mRNA of PCA3, hk2, and miRNA-141 in peripheral blood. At the same time, analyze those clinical outcomes used in the patients. We compared these different outcomes to evaluate the value of new molecular markers.
RESULTS: The level of mRNA of PCA3, hK2, and miR-141 in Pca group were significantly higher than that in BPH. PSA had the highest sensitivity in predicting Pca diagnosis (76.7%); PCA3 had the highest specificity (82.5%). And the combination of PCA3, PSA, and hK2 improved area under the curve (AUC)-receiver operating characteristic (ROC) curve largely, especially those with PSA 4-10ng/mL.
CONCLUSIONS: PCA3, hK2, and miRNA-141 were biomarkers of Pca with potential clinical application value, especially in patients with PSA gray area. Combining PCA3, PSA, and hK2 performed better than individual biomarkers alone in predicting Pca.

Hernandez J, Gelfond J, Goros M, et al.
The effect of 3-month finasteride challenge on biomarkers for predicting cancer outcome on biopsy: Results of a randomized trial.
PLoS One. 2018; 13(10):e0204823 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Finasteride, a 5-alpha reductase inhibitor may have effects on biomarkers such as prostate-specific antigen (PSA) that could be leveraged to improve screening.
OBJECTIVE: To determine the predictive characteristics of biomarkers for prostate cancer for cancer on biopsy following 3 months of finasteride use compared with placebo.
DESIGN, SETTING AND PARTICIPANTS: 383 men from multiple clinical sites with intermediate prostate cancer risk, without history of prostate cancer, were randomly allocated in a double-blinded manner, 4:1, to receive either finasteride or placebo for 90 days at which time a prostate biopsy was performed.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcomes were associations of biomarkers with prostate cancer that were tested using multiple logistic regression and area under the receiver operating curves (AUC). Biomarkers for PCA risk (PCA3, TMPRSS2:ERG (T2:ERG) gene product, and PSA) were measured at baseline and at biopsy in a blinded fashion to assess the predictive performance of baseline levels, 90-day levels, and measures of change relative to standard predictors.
RESULTS AND LIMITATIONS: A total of 292 (233 finasteride; 59 placebo) randomized patients underwent biopsy and were analyzed. On finasteride, baseline and 90-day measures of PCA3 and T2:ERG had similar moderate discrimination capacity with AUCs 62 to 65% (p-values < 0.001 and 0.001, respectively), but their rates of change had no discrimination ability (AUC 51%, (95% CI 43 to 60% p = 0.72) and 48% (95% CI 44 to 60%, p = 0.62), respectively).) Relative to baseline, the 90-day PCA3 and PSA decreased in the finasteride group by 25% and 50%, respectively (both p<0.001). T2:ERG had a smaller, non-significant change post finasteride treatment (p = 0.08).
CONCLUSIONS: Short-term finasteride therapy did not improve performance of the most commonly-employed prostate cancer biomarkers. Threshold values for new biomarkers of prostate cancer should be interpreted with caution in patients receiving finasteride until formal validation of test performance in these patients is conducted.
PATIENT SUMMARY: Three months of finasteride treatment did not increase the accuracy for predicting the outcome on prostate biopsy but did have a significant effect on biomarker values. Adjustments to thresholds for biopsy for men on finasteride are proposed.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT01296672.

Filella X, Foj L
Novel Biomarkers for Prostate Cancer Detection and Prognosis.
Adv Exp Med Biol. 2018; 1095:15-39 [PubMed] Related Publications
Prostate cancer (PCa) remains as one of the most controversial issues in health care because of the dilemmas related to screening using Prostate Specific Antigen (PSA). A high number of false positive biopsies and an elevated rate of overdiagnosis are the main problems associated with PSA. New PCa biomarkers have been recently proposed to increase the predictive value of PSA. The published results showed that PCA3 score, Prostate Health Index and 4Kscore can reduce the number of unnecessary biopsies, outperforming better than PSA and the percentage of free PSA. Furthermore, 4Kscore provides with high accuracy an individual risk for high-grade PCa. High values of PHI are also associated with tumor aggressiveness. In contrast, the relationship of PCA3 score with aggressiveness remains controversial, with studies showing opposite conclusions. Finally, the development of molecular biology has opened the study of genes, among them TMPRSS2:ERG fusion gene and miRNAs, in PCa detection and prognosis.

Sajjadi E, Atashi A, Tajrishi MAMH, Saei Z
Gene expression analysis of noncoding PCA3 gene in patients with chronic myeloid leukemia.
J Cancer Res Ther. 2018 Jul-Sep; 14(5):1079-1082 [PubMed] Related Publications
Introduction and Objectives: Nowadays, noncoding RNAs are of special significance to scientists. Among RNAs, long noncoding RNAs (lncRNAs) have an important role in gene expression regulation. Recent studies show aberrant lncRNAs expression in different types of cancer including blood malignancies. As such, lncRNAs could be a possible way for diagnosis and treatment of certain cancers. In the current study, the level of PCA3 gene expression in patients with chronic myeloid leukemia (CML) was compared with normal individuals to find out whether the level of PCA3 in CML patients is increased according to our hypothesis.
Materials and Methods: The buffy coat was collected from peripheral blood of thirty untreated CML patients (BCR-ABL positive) and twenty normal volunteers. RNA was extracted from white blood cells and cDNA was synthesized. The level of PCA3 gene expression was measured using quantitative reverse transcription-polymerase chain reaction.
Results: The results showed that PCA3 has expression in both normal and leukemic white blood cells. The data also revealed higher expression of PCA3 in leukemic patients, compared to the normal counterpart (P < 0.05).
Conclusion: The unusual increase in PCA3 gene expression in CML patients suggests the need for more research on mechanisms of molecular pathways related to PCA3 which could help achieve better treatment.

Li Y, Yang Z
Analysis of competing endogenous RNA network to identify the key RNAs associated with prostate adenocarcinoma.
Pathol Res Pract. 2018; 214(11):1811-1817 [PubMed] Related Publications
OBJECTIVES: Prostate adenocarcinoma (PRAD) is the most common cancer in men. The aim of this study was to reveal the critical long non-coding RNA (lncRNAs), microRNA (miRNAs) and mRNAs involved in the pathogenesis of PRAD.
METHODS: The level 3 mRNA and miRNA sequencing data of PRAD were downloaded from The Cancer Genome Atlas database. Using the edgeR package of R, the differentially expressed mRNAs (DEGs), lncRNAs (DE-lncRNAs) and miRNAs (DE-miRNAs) between PRAD and normal tissues were screened. The Cox proportional hazards regression method in the survival package was used to select the lncRNAs significantly related to clinical characteristics. After the miRNA-lncRNA and miRNA-mRNA pairs were predicted, a regulatory network was constructed by the Cytoscape software. For the DEGs involved in the network, enrichment analysis was conducted by the Fisher algorithm.
RESULTS: Compared to the normal samples, 25 DE-lncRNAs, 1421 DEGs and 68 DE-miRNAs were identified in the PRAD samples. The down-regulated MESTIT1 had a significantly negative correlation with overall survival. A total of 44 DE-miRNA-DE-lncRNA pairs were predicted, including the PCA3-miR-96 and UCA1-miR-96. Meanwhile, 33 DEGs targeted by miRNAs (for example, miR-96-CYP19A1) were found to correlate with cancers.
CONCLUSION: Functional enrichment analysis showed that the reproductive development process (which involved TDRD1) was enriched for the DEGs implicated in the lncRNA-miRNA-mRNA regulatory network. The lncRNAs MESTIT1, PCA3, and UCA1; mRNAs CYP19A1 and TDRD1; as well as miR-96 might affect the pathogenesis of PRAD.

Fujita K, Nonomura N
Urinary biomarkers of prostate cancer.
Int J Urol. 2018; 25(9):770-779 [PubMed] Related Publications
The development of more specific biomarkers for prostate cancer and/or high-risk prostate cancer is necessary, because the prostate-specific antigen test lacks specificity for the detection of prostate cancer and can lead to unnecessary prostate biopsies. Urine is a promising source for the development of new biomarkers of prostate cancer. Biomarkers derived from prostate cancer cells are released into prostatic fluids and then into urine. Urine after manipulation of the prostate is enriched with prostate cancer biomarkers, which include prostate cancer cells, DNAs, RNAs, proteins and other small molecules. The urinary prostate cancer antigen 3 test is the first Food and Drug Administration-approved RNA-based urinary marker, and it helps in the detection of prostate cancer on repeat biopsy. The SelectMDx test is based on messenger RNA detection of DLX1 and HOXC6 in urine after prostate massage, and helps in the detection of high-risk prostate cancer on prostate biopsy. Exosomes are extracellular vesicles with a diameter of 30-200 nm that are secreted from various types of cells. Urinary prostate cancer-derived exosomes also contain RNAs and proteins specific for prostate cancer (e.g. PCA3 and TMPRSS2-ERG), and could be promising sources of novel biomarker discovery. The ExoDx Prostate test is a commercially available test based on the detection of three genes (PCA3, ERG and SPDEF) in urinary exosomes. Advancement of comprehensive analysis (microarray, mass spectrometry and next-generation sequencing) has resulted in the discovery of several urinary biomarkers. Non-invasive urinary markers can help in the decision to carry out prostate biopsy or in the design of a therapeutic strategy.

Li M, Zhou D, Zhang W, et al.
Urine PCA3 mRNA level in diagnostic of prostate cancer.
J Cancer Res Ther. 2018; 14(4):864-866 [PubMed] Related Publications
Objective: The objective of this study is to evaluate the diagnostic effects of urine PCA3 mRNA level in patients with prostate cancer (PC).
Methods: Twenty four patients with pathologically confirmed PC, 40 patients with benign prostatic hyperplasia (BPH), and 13 patients with urolithiasis were recruited in this study. The urine level of PCA3 mRNA was determined with real-time polymerase chain reaction and compared among the three groups. With the reference parameter of urine PCA3 mRNA, the diagnostic sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated.
Results: The mRNA level in urine of PC, BPH and urolithiasis were 60.2 ± 32.2, 17.1 ± 12.9, and 6.2 ± 3.1, respectively, indicating that mRNA level in PC was significantly higher than that of in other two groups (P < 0.05). The AUC was 0.90 while the sensitivity and specificity were 87.5% and 79.2% with the cutoff value of 33.86.
Conclusion: The urine PCA3 mRNA could be a biomarker for diagnosing patients with PC.

Gerashchenko GV, Mevs LV, Chashchina LI, et al.
Expression of steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes in prostate tumors in relation to the presence of the TMPRSS2/ERG fusion.
Exp Oncol. 2018; 40(2):101-108 [PubMed] Related Publications
AIM: To analyze an expression pattern of the steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes in prostate tumors in relation to the presence of the TMPRSS2/ERG fusion; and to examine a putative correlation between gene expression and clinical characteristics, to define the molecular subtypes of prostate cancer.
MATERIALS AND METHODS: The relative gene expression (RE) of 33 transcripts (27 genes) and the presence/absence of the TMPRSS2/ERG fusion were analyzed by a quantitative PCR. 37 prostate cancer tissues (T) paired with conventionally normal prostate tissue (CNT) and 21 samples of prostate adenomas were investigated. RE changes were calculated, using different protocols of statistics.
RESULTS: We demonstrated differences in RE of seven genes between tumors and CNT, as was calculated, using the 2-ΔCT model and the Wilcoxon matched paired test. Five genes (ESR1, KRT18, MKI67, MMP9, PCA3) showed altered expression in adenocarcinomas, in which the TMPRSS2/ERG fusion was detected. Two genes (INSR, isoform B and HOTAIR) expressed differently in tumors without fusion. Comparison of the gene expression pattern in adenomas, CNT and adenocarcinomas demonstrated that in adenocarcinomas, bearing the TMPRSS2/ERG fusion, genes KRT18, PCA3, and SCHLAP1 expressed differently. At the same time, we detected differences in RE of AR (isoform 2), MMP9, PRLR and HOTAIR in adenocarcinomas without the TMPRSS2/ERG fusion. Two genes (ESR1 and SRD5A2) showed differences in RE in both adenocarcinoma groups. Fourteen genes, namely AR (isoforms 1 and 2), CDH1, OCLN, NKX3-1, XIAP, GCR (ins AG), INSR (isoform A), IGF1R, IGF1R tr, PRLR, PRL, VDR and SRD5A2 showed correlation between RE and tumor stage. RE of four genes (CDH2, ESR2, VDR and SRD5A2) correlated with differentiation status of tumors (Gleason score). Using the K-means clustering, we could cluster adenocarcinomas in three groups, according to gene expression profiles. A specific subtype of prostate tumors is characterized by the activated ERG signaling, due to the presence of TMPRSS2/ERG fusion, and also by high levels of the androgen receptor, prolactin, IGF, INSR and PCA3.
CONCLUSIONS: We have found the specific differences in expression of the steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes, depending on the pre-sence/absence of the TMPRSS2/ERG fusion in prostate adenocarcinomas, CNT and adenomas. We showed three different gene expression profiles of prostate adenocarcinomas. One of them is characteristic for adenocarcinomas with the TMPRSS2/ERG fusion. Further experiments are needed to confirm these data in a larger cohort of patients.

Cao D, Gu C, Ye D, et al.
PCA3 rs544190G>A and prostate cancer risk in an eastern Chinese population.
Int Braz J Urol. 2018 May-Jun; 44(3):500-505 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The association of prostate cancer antigen 3 (PCA3) polymorphism (SNP, rs544190G>A) with metastatic prostate cancer in European descent has been reported. Our aim of the current study was to re-validate the effect of PCA3 polymorphism on prostate cancer risk in an Eastern Chinese population and then estimate possible genetic discrepancies among population.
MATERIALS AND METHODS: Taqman assay was employed to determine genotype of SNP rs544190 in 1015 ethnic Han Chinese patients with prostate cancer and 1032 cancerfree controls. Simultaneously, odds ratios (OR) and 95% confidence intervals (95%CI) for risk relationship were calculated by logistic regression models.
RESULTS: The statistically significant relationship between PCA3 rs544190G>A and higher prostate cancer risk was not found. Stratification analysis revealed that there was no remarkable association of rs544190 variant AG/AA genotype with prostate cancer risk in every subgroup, except for patients with Gleason score ≤7(3+4).
CONCLUSION: Although the results demonstrated that SNP rs544190 was not involved in prostate cancer risk in Eastern Chinese descent, unlike in European population, these might have clinical implications on prostate cancer heterogeneity around the World. To validate these findings, well-designed studies with different ethnic populations are warranted.

Zhao H, Ma TF, Lin J, et al.
Identification of valid reference genes for mRNA and microRNA normalisation in prostate cancer cell lines.
Sci Rep. 2018; 8(1):1949 [PubMed] Free Access to Full Article Related Publications
RT-qPCR offers high sensitivity, for accurate interpretations of qPCR results however, normalisation using suitable reference genes is fundamental. Androgens can regulate transcriptional expression including reference gene expression in prostate cancer. In this study, we evaluated ten mRNA and six non-protein coding RNA reference genes in five prostate cell lines under varied dihydrotestosterone (DHT) treatments. We validated the effects of DHT-treatments using media containing charcoal-stripped serum prior to DHT stimulation on the test samples by Western blot experiments. Reference gene expression stability was analysed using three programs (geNorm, NormFinder and BestKeeper), and the recommended comprehensive ranking is provided. Our results reveal that ACTB and GAPDH, and miR-16 and miR-1228-3p are the most suitable mRNA and miRNA reference genes across all cell lines, respectively. Considering prostate cancer cell types, ACTB/GAPDH and ACTB/HPRT1 are the most suitable reference gene combinations for mRNA analysis, and miR-16/miR-1228-3p and RNU6-2/RNU43 for miRNA analysis in AR+, and AR- and normal cell lines, respectively. Comparison of relative target gene (PCA3 and miR-141) expression reveals different patterns depending on reference genes used for normalisation. To our knowledge, this is the first report on validation of reference genes under different DHT treatments in prostate cancer cells. This study provides insights for discovery of reliable DHT-regulated genes in prostate cells.

Gutschner T, Richtig G, Haemmerle M, Pichler M
From biomarkers to therapeutic targets-the promises and perils of long non-coding RNAs in cancer.
Cancer Metastasis Rev. 2018; 37(1):83-105 [PubMed] Related Publications
Biomarker-driven personalized cancer therapy is a field of growing interest, and several molecular tests have been developed to detect biomarkers that predict, e.g., response of cancers to particular therapies. Identification of these molecules and understanding their molecular mechanisms is important for cancer prognosis and the development of therapeutics for late stage diseases. In the past, significant efforts have been placed on the discovery of protein or DNA-based biomarkers while only recently the class of long non-coding RNA (lncRNA) has emerged as a new category of biomarker. The mammalian genome is pervasively transcribed yielding a vast amount of non-protein-coding RNAs including lncRNAs. Hence, these transcripts represent a rich source of information that has the potential to significantly contribute to precision medicine in the future. Importantly, many lncRNAs are differentially expressed in carcinomas and they are emerging as potent regulators of tumor progression and metastasis. Here, we will highlight prime examples of lncRNAs that serve as marker for cancer progression or therapy response and which might represent promising therapeutic targets. Furthermore, we will introduce lncRNA targeting tools and strategies, and we will discuss potential pitfalls in translating these into clinical trials.

Lai J, Moya L, An J, et al.
A microsatellite repeat in PCA3 long non-coding RNA is associated with prostate cancer risk and aggressiveness.
Sci Rep. 2017; 7(1):16862 [PubMed] Free Access to Full Article Related Publications
Short tandem repeats (STRs) are repetitive sequences of a polymorphic stretch of two to six nucleotides. We hypothesized that STRs are associated with prostate cancer development and/or progression. We undertook RNA sequencing analysis of prostate tumors and adjacent non-malignant cells to identify polymorphic STRs that are readily expressed in these cells. Most of the expressed STRs in the clinical samples mapped to intronic and intergenic DNA. Our analysis indicated that three of these STRs (TAAA-ACTG2, TTTTG-TRIB1, and TG-PCA3) are polymorphic and differentially expressed in prostate tumors compared to adjacent non-malignant cells. TG-PCA3 STR expression was repressed by the anti-androgen drug enzalutamide in prostate cancer cells. Genetic analysis of prostate cancer patients and healthy controls (N > 2,000) showed a significant association of the most common 11 repeat allele of TG-PCA3 STR with prostate cancer risk (OR = 1.49; 95% CI 1.11-1.99; P = 0.008). A significant association was also observed with aggressive disease (OR = 2.00; 95% CI 1.06-3.76; P = 0.031) and high mortality rates (HR = 3.0; 95% CI 1.03-8.77; P = 0.045). We propose that TG-PCA3 STR has both diagnostic and prognostic potential for prostate cancer. We provided a proof of concept to be applied to other RNA sequencing datasets to identify disease-associated STRs for future clinical exploratory studies.

Xu W, Foster BA, Richards M, et al.
Characterization of prostate cancer cell progression in zebrafish xenograft model.
Int J Oncol. 2018; 52(1):252-260 [PubMed] Free Access to Full Article Related Publications
Early diagnosis of prostate cancer (PCa) is critical for the application of efficient treatment to PCa patients. However, the majority of PCas remains indolent from several months to several years before malignancy. Current diagnosis methods have limitations in their reliability and are inefficient in time cost. Thus, an efficient in vivo PCa cell xenograft model is highly desired for diagnostic studies in PCas. In the present study we present a standardized procedure to create a PCa cell xenograft model using zebrafish (Danio rerio) as the host. PC3-CTR cells, a cell line from adenocarcinoma with stable expression of calcitonin receptor (CRT), were subcutaneously injected into zebrafish larvae at 48 h post fertilization. The nursing conditions for the larvae were optimized with stable survival rates of post hatch and post PC3-CTR cell injection. In this system, the progression of PC3-CTR cells in vivo was evaluated by migration and proliferation of the cells. Massive migrations of PC3 cells in vivo were observed at post injection day (PID)3. The injected PC3-CTR cells eventually invaded the whole larval zebrafish at PID5. Quantification of PC3-CTR cell proliferation was done using quantitative PCR (qPCR) analysis targeting the expression profiles of two PCa housekeeping genes, TATA-binding protein (TBP) and hypoxanthine phosphoribosyltransferase 1 (HPRT1) encoding genes. The excessive proliferation of PC3 cells in vivo was detected with both qPCR assays. Expression levels of one non‑coding gene, prostate cancer associated 3 gene (pca3), and two other genes encoding transient receptor potential ion channel Melastatin 8 (trpm8) and prostate-specific membrane antigen (psma), showed a significantly enhanced aggressiveness of PC3-CTR cells in vivo. The model established in the present study provides an improved in vivo model for the diagnosis of PCas efficiently. This PCa cell xenograft model can also serve as a tool for high throughput anti-PCa drug screening in therapeutic treatments.

Wu D, Ni J, Beretov J, et al.
Urinary biomarkers in prostate cancer detection and monitoring progression.
Crit Rev Oncol Hematol. 2017; 118:15-26 [PubMed] Related Publications
Prostate cancer (CaP) is the most common cancer in men and the second leading cause of cancer deaths in males in Australia. Although serum prostate-specific antigen (PSA) has been the most widely used biomarker in CaP detection for decades, PSA screening has limitations such as low specificity and potential association with over-diagnosis. Current biomarkers used in the clinic are not useful for the early detection of CaP, or monitoring its progression, and have limited value in predicting response to treatment. Urine is an ideal body fluid for the detection of protein markers of CaP and is emerging as a potential source for biomarker discovery. Gene-based biomarkers in urine such as prostate cancer antigen-3 (PCA3), and genes for transmembrane protease serine-2 (TMPRSS2), and glutathione S-transferase P (GSTP1) have been developed and evaluated in the past decades. Among these biomarkers, urinary PCA3 is the only one approved by the FDA in the USA for clinical use. The study of urine microRNAs (miRNAs) is another burgeoning area for investigating biomarkers to achieve a pre-biopsy prediction of CaP to contribute to early detection. The development of mass spectrometry (MS)-based proteomic techniques has sparked new searches for novel protein markers for many diseases including CaP. Urinary biomarkers for CaP represent a promising alternative or an addition to traditional biomarkers. Future success in biomarker discovery will rely on collaboration between clinics and laboratories. In addition, research efforts need to be moved from biomarker discovery to validation in a large cohort or separate population of patients and translation of these findings to clinical practice. In this review, we discuss urine as a potential source for CaP biomarker discovery, summarise important genetic urine biomarkers in CaP and focus on MS-based proteomic approaches as well as other recent developments in quantitative techniques for CaP urine biomarker discovery.

Liu Y, Zong ZH, Guan X, et al.
The role of long non-coding RNA PCA3 in epithelial ovarian carcinoma tumorigenesis and progression.
Gene. 2017; 633:42-47 [PubMed] Related Publications
OBJECTIVES: Ovarian carcinoma is one of the highest incidence of tumors in women, and the generation, development and prognosis of epithelial ovarian carcinoma (EOC) remains an open field of study. The role of long non-coding RNAs (lncRNAs) in epithelial ovarian carcinoma is an emerging area of research.
MATERIALS AND METHODS: LncRNA PCA3 expression was determined in EOC and normal ovarian tissues by RT-PCR. Phenotypes indicative of tumor progression and aggressiveness, including cell proliferation, migration, invasion, and expression of related molecules, were analysed in EOC cell following knockdown of lncRNA PCA3 by transfection with small interfering RNA (siRNA).
RESULTS: Expression of lncRNA PCA3 in epithelial ovarian cancer tissues was higher than in normal ovarian tissue. We discovered that knockdown of lncRNA PCA3 in EOC cells by siRNA transfection significantly suppressed cell proliferation, migration, and invasion. Bioinformatic predictions and dual-luciferase reporter assays indicate that the 3'UTR of PCA3 has potential binding sites for miR-106b-5p. Knockdown of the lncRNA PCA3 by siRNA resulted in up-regulated miR-106b expression. In addition, knockdown of PCA3 also reduced protein expression of Ras homolog gene family member C (RhoC), Bcl/xl, P70 ribosomal S6 kinase (P70S6K), and Matrix metallopeptidase 2 (MMP2), which are regulated by miR-106b.
CONCLUSIONS: Research results show that lncRNA PCA3 may coordinate EOC tumorigenesis through disrupting miR-106b regulated gene expression. PCA3 may be a novel and important diagnostic biomarker and a valuable marker for prediction in the clinical care of epithelial ovarian carcinoma.

Kyriakou IK, Mavridis K, Kalogianni DP, et al.
Multianalyte quantitative competitive PCR on optically encoded microspheres for an eight-gene panel related to prostate cancer.
Anal Bioanal Chem. 2018; 410(3):971-980 [PubMed] Related Publications
Nucleic acid-based tests have a profound impact in every medical discipline. Because multigene tests offer higher diagnostic accuracy and lower overall cost than single assays, they are especially useful for diseases, like prostate cancer, that present variability at the molecular level and diversity of available therapeutic interventions. We have developed a quantitative competitive PCR for an eight-gene panel, related to prostate cancer, that includes five genes of the human tissue kallikrein family (KLKs), prostate-specific membrane antigen (PSMA), prostate cancer antigen 3 (PCA3), and HPRT1 as a reference gene. Using PCR as a synthetic tool, a competitor was prepared for each target sequence containing the same primer binding sites as the target but differing in a short segment to enable discrimination by hybridization. The assay involves multiplex amplification of targets and competitors followed by a multiplex hybridization assay for the 16 amplification products. The assay was performed on optically encoded microspheres with oligonucleotide probes attached to their surface. The microspheres were analyzed rapidly (1 min) by flow cytometry. The signal ratio of the target and cognate competitor is a function of the target copy number in the sample prior to amplification. The multiplexing potential of the proposed method is much higher than real-time PCR and other end-point methods since there are 100 sets of commercially available microspheres.

Lin C, Wang J, Wang Y, et al.
GRP78 Participates in PCA3-regulated Prostate Cancer Progression.
Anticancer Res. 2017; 37(8):4303-4310 [PubMed] Related Publications
BACKGROUND/AIM: The human prostate cancer antigen 3 (PCA3) is a long non-coding RNA (lncRNA) commonly used as a diagnostic marker for prostate cancer (PCa). Herein we investigated the cellular function of PCA3 in PCa and its potential mechanism.
MATERIALS AND METHODS: PCA3 was overexpressed in a PC3 cell line (PC3
RESULTS: Overexpression of PCA3 significantly increased cell proliferation rate, migration and invasion, while inhibited apoptosis in PC3 cells. Three proteins were found down-regulated and 7 proteins up-regulated in PC3
CONCLUSION: This study confirmed that in PCa, PCA3 plays a pro-cancer role through promoting cell proliferation, migration and invasion while inhibiting cell apoptosis. This process might involve the up-regulation of GRP78.

Özgür E, Celik AI, Darendeliler E, Gezer U
Anticancer Res. 2017; 37(7):3631-3637 [PubMed] Related Publications
BACKGROUND/AIM: Prostate cancer (PCa) is an androgen-dependent disease. Novel anti-androgens (i.e. enzalutamide) have recently been developed for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Evidence is accumulating that prostate cancer antigen 3 (PCA3) is involved in androgen receptor (AR) signaling. Here, in combination with enzalutamide-mediated AR blockade, we investigated the effect of PCA3 targeting on the viability of PCa cells.
MATERIALS AND METHODS: In hormone-sensitive LNCaP cells, AR-overexpressing LNCaP-AR
RESULTS: PCA3 targeting reduced the expression of AR-related genes (i.e. prostate-specific antigen (PSA) and prostate-specific transcript 1 (non-protein coding) (PCGEM1)) and potentiated the effect of enzalutamide. Proliferation of PCa cells was suppressed upon PCA3 silencing with a greater effect in LNCaP-AR
CONCLUSION: PCA3, as a therapeutic target in PCa, might be used to potentiate AR antagonists.

Giunchi F, Ciccarese C, Montironi R, et al.
Urinary Biomarkers for Prostate Cancer.
Curr Drug Metab. 2017; 18(8):723-726 [PubMed] Related Publications
BACKGROUND: Urine may represent a convenient source of biomarkers for the early detection of Prostate Cancer (PCa) since it contains secreted prostatic products and exfoliated tumor cells. Furthermore, urine is easy to collect with non-invasive procedures which are repeatable.
METHOD: Several urinary biomarkers for PCa have been proposed in the past but only one (PCA3) has been approved for clinical use and even this is not widely utilized in the routine practice. Most of these, particularly the proteins, were abandoned due to lack of confirmation. DNA markers have been proposed but they are less suitable compared to other malignancies, such as bladder cancer due to the limited amount of DNA somatic alterations in PCa compared to gene fusions and pathway activations.
CONCLUSION: RNA biomarkers are still the most promising and particularly miRNA and AMACR mRNA but the main weaknesses that prevented the full clinical implementation are the absence of a validated of the cut-off levels and the identification of consistent reference standards.

Pellegrini KL, Patil D, Douglas KJS, et al.
Detection of prostate cancer-specific transcripts in extracellular vesicles isolated from post-DRE urine.
Prostate. 2017; 77(9):990-999 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The measurement of gene expression in post-digital rectal examination (DRE) urine specimens provides a non-invasive method to determine a patient's risk of prostate cancer. Many currently available assays use whole urine or cell pellets for the analysis of prostate cancer-associated genes, although the use of extracellular vesicles (EVs) has also recently been of interest. We investigated the expression of prostate-, kidney-, and bladder-specific transcripts and known prostate cancer biomarkers in urine EVs.
METHODS: Cell pellets and EVs were recovered from post-DRE urine specimens, with the total RNA yield and quality determined by Bioanalyzer. The levels of prostate, kidney, and bladder-associated transcripts in EVs were assessed by TaqMan qPCR and targeted sequencing.
RESULTS: RNA was more consistently recovered from the urine EV specimens, with over 80% of the patients demonstrating higher RNA yields in the EV fraction as compared to urine cell pellets. The median EV RNA yield of 36.4 ng was significantly higher than the median urine cell pellet RNA yield of 4.8 ng. Analysis of the post-DRE urine EVs indicated that prostate-specific transcripts were more abundant than kidney- or bladder-specific transcripts. Additionally, patients with prostate cancer had significantly higher levels of the prostate cancer-associated genes PCA3 and ERG.
CONCLUSIONS: Post-DRE urine EVs are a viable source of prostate-derived RNAs for biomarker discovery and prostate cancer status can be distinguished from analysis of these specimens. Continued analysis of urine EVs offers the potential discovery of novel biomarkers for pre-biopsy prostate cancer detection.

Pang KH, Rosario DJ, Morgan SL, Catto JW
Evaluation of a short RNA within Prostate Cancer Gene 3 in the predictive role for future cancer using non-malignant prostate biopsies.
PLoS One. 2017; 12(4):e0175070 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Prostate Cancer 3 (PCA3) is a long non-coding RNA (ncRNA) upregulated in prostate cancer (PCa). We recently identified a short ncRNA expressed from intron 1 of PCA3. Here we test the ability of this ncRNA to predict the presence of cancer in men with a biopsy without PCa.
METHODS: We selected men whose initial biopsy did not identify PCa and selected matched cohorts whose subsequent biopsies revealed PCa or benign tissue. We extracted RNA from the initial biopsy and measured PCA3-shRNA2, PCA3 and PSA (qRT-PCR).
RESULTS: We identified 116 men with and 94 men without an eventual diagnosis of PCa in 2-5 biopsies (mean 26 months), collected from 2002-2008. The cohorts were similar for age, PSA and surveillance period. We detected PSA and PCA3-shRNA2 RNA in all samples, and PCA3 RNA in 90% of biopsies. The expression of PCA3 and PCA3-shRNA2 were correlated (Pearson's r = 0.37, p<0.01). There was upregulation of PCA3 (2.1-fold, t-test p = 0.02) and PCA3-shRNA2 (1.5-fold) in men with PCa on subsequent biopsy, although this was not significant for the latter RNA (p = 0.2). PCA3 was associated with the future detection of PCa (C-index 0.61, p = 0.01). This was not the case for PCA3-shRNA2 (C-index 0.55, p = 0.2).
CONCLUSIONS: PCA3 and PCA3-shRNA2 expression are detectable in historic biopsies and their expression is correlated suggesting co-expression. PCA3 expression was upregulated in men with PCa diagnosed at a future date, the same did not hold for PCA3-shRNA2. Futures studies should explore expression in urine and look at a time course between biopsy and PCa detection.

Neumann E, Hennenlotter J, Todenhöfer T, et al.
The Value and Evaluability of the PCA3 Urine Assay in Prostate Carcinoma is Independent of the Tumor Localization.
Adv Ther. 2017; 34(4):966-974 [PubMed] Related Publications
INTRODUCTION: The prostate cancer gene 3 (PCA3) test is based on the analysis of tumor cell mRNA in urine. As an exprimated urinary marker, its retrieval is subject to certain physical aspects like palpation pressure and detachment force during the squeezing of cells. Other potential factor of influence may be the distance the cells have to cover until they reach the urethra. Thus, it was investigated whether the localization of the tumors within the prostate with regard to the urethra and the seminal colliculus influences the PCA3 score.
METHODS: Prostatectomy specimens of 55 organ-confined prostate cancer patients were processed according to the Stanford protocol. For each prostatectomy specimen, a three-dimensional reconstruction including the surface of the prostate, the tumor areas and the urethra was created. By model simulating, virtual concentric tubes were placed around the urethra and spherical volumes were virtually positioned around the seminal colliculus at diameters of 8, 16 and 32 mm. Depending on localization, tumor volumes may or may not protrude into the tubes or spherical volumes. For each respective diameter, PCA3 levels were compared between the subgroup with and without protrusion of tumor tissue into the tube or spherical ball.
RESULTS: For none of the diameters, whether in tubes or spherical balls, were patients without intersection volumes-hence showing peripherally located tumors-found to have lower PCA3 levels. No clinical or histopathological parameter correlated with the PCA3 score.
CONCLUSION: The location of the tumor mass in the prostate with respect to the urethra or the seminal colliculus did not to affect the PCA3 score. Hence, the location of the tumor does not limit the validity of the PCA3 score, and even for exclusively peripherall y located tumors, this possible influencing factor did not lead to an artificial modulation of the PCA3 score.

Smolle MA, Bauernhofer T, Pummer K, et al.
Current Insights into Long Non-Coding RNAs (LncRNAs) in Prostate Cancer.
Int J Mol Sci. 2017; 18(2) [PubMed] Free Access to Full Article Related Publications
The importance of long non-coding RNAs (lncRNAs) in the pathogenesis of various malignancies has been uncovered over the last few years. Their dysregulation often contributes to or is a result of tumour progression. In prostate cancer, the most common malignancy in men, lncRNAs can promote castration resistance, cell proliferation, invasion, and metastatic spread. Expression patterns of lncRNAs often change during tumour progression; their expression levels may constantly rise (e.g., HOX transcript antisense RNA, HOTAIR), or steadily decrease (e.g., downregulated RNA in cancer, DRAIC). In prostate cancer, lncRNAs likewise have diagnostic (e.g., prostate cancer antigen 3, PCA3), prognostic (e.g., second chromosome locus associated with prostate-1, SChLAP1), and predictive (e.g., metastasis-associated lung adenocarcinoma transcript-1, MALAT-1) functions. Considering their dynamic role in prostate cancer, lncRNAs may also serve as therapeutic targets, helping to prevent development of castration resistance, maintain stable disease, and prohibit metastatic spread.

Dani H, Loeb S
The role of prostate cancer biomarkers in undiagnosed men.
Curr Opin Urol. 2017; 27(3):210-216 [PubMed] Free Access to Full Article Related Publications
PURPOSE OF REVIEW: This article intends to review biomarkers derived from blood, urine, and tissue that can aid in the diagnosis of prostate cancer (PCa).
RECENT FINDINGS: PCa screening requires tools that complement prostate-specific antigen (PSA) with a higher specificity for clinically significant disease. Novel blood biomarkers, such as the Prostate Health Index (phi) and 4Kscore, utilize isoforms of PSA to more accurately predict high-grade PCa than traditional tools such as PSA and the percentage free-to-total PSA. Several gene products associated with PCa can be detected in the urine through commercially available assays. PCa antigen 3 (PCA3), though approved for repeat biopsy decisions, appears inferior to other biomarkers such as phi for identifying aggressive disease. However, combinations of PCA3 with other urine assays have shown promising results. One tissue-based hypermethylation test, named ConfirmMDx, can also be used to determine the need for repeat biopsy in men with a prior negative biopsy.
SUMMARY: Several biomarkers have been developed to aid in the screening and diagnosis of PCa. Such tests are often indicated in men with moderately elevated PSA or history of a prior negative biopsy. Their use facilitates reduction of unnecessary biopsies without sacrificing the early diagnosis of clinically significant PCa.

O'Malley PG, Nguyen DP, Al Hussein Al Awamlh B, et al.
Racial Variation in the Utility of Urinary Biomarkers PCA3 and T2ERG in a Large Multicenter Study.
J Urol. 2017; 198(1):42-49 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To our knowledge it is unknown whether urinary biomarkers for prostate cancer have added utility to clinical risk calculators in different racial groups. We examined the utility of urinary biomarkers added to clinical risk calculators for predicting prostate cancer in African American and nonAfrican American men.
MATERIALS AND METHODS: Demographics, PCPT (Prostate Cancer Prevention Trial) risk scores, data on the biomarkers data PCA3 (prostate cancer antigen 3) and T2ERG (transmembrane protease serine 2 and v-ets erythroblastosis virus E26 oncogene homolog gene fusion), and biopsy pathology features were prospectively collected on 718 men as part of EDRN (Early Detection Research Network). Utility was determined by generating ROC curves and comparing AUC values for the baseline multivariable PCPT model and for models containing biomarker scores.
RESULTS: PCA3 and T2ERG added utility for the prediction of prostate cancer and clinically significant prostate cancer when combined with the PCPT Risk Calculator. This utility was seen in nonAfrican American men only for PCA3 (AUC 0.64 increased to 0.75 for prostate cancer and to 0.69-0.77 for clinically significant prostate cancer, both p <0.001) and for T2ERG (AUC 0.64-0.74 for prostate cancer, p <0.001, and 0.69-0.73 for clinically significant prostate cancer, p = 0.029). African American men did not have an added benefit with the addition of biomarkers, including PCA3 (AUC 0.75-0.77, p = 0.64, and 0.65-0.66, p = 0.74) and T2ERG (AUC 0.75-0.74, p = 0.74, and 0.65-0.64, p = 0.88), for prostate cancer and clinically significant prostate cancer, respectively. Limitations include the small number of African American men (72). The post hoc subgroup analysis nature of the study limited findings to being hypothesis generating.
CONCLUSIONS: As novel biomarkers are discovered, clinical utility should be established across demographically diverse cohorts.

Tanase CP, Codrici E, Popescu ID, et al.
Prostate cancer proteomics: Current trends and future perspectives for biomarker discovery.
Oncotarget. 2017; 8(11):18497-18512 [PubMed] Free Access to Full Article Related Publications
The clinical and fundamental research in prostate cancer - the most common urological cancer in men - is currently entering the proteomic and genomic era. The focus has switched from one single marker (PSA) to panels of biomarkers (including proteins involved in ribosomal function and heat shock proteins). Novel genetic markers (such as Transmembrane protease serine 2 (TMPRSS2)-ERG fusion gene mRNA) or prostate cancer gene 3 (PCA3) had already entered the clinical practice, raising the question whether subsequent protein changes impact the evolution of the disease and the response to treatment. Proteomic technologies such as MALDI-MS, SELDI-MS, i-TRAQ allow a qualitative/quantitative analysis of the proteome variations, in both serum and tumor tissue. A new trend in prostate cancer research is proteomic analysis of prostasomes (prostate-specific exosomes), for the discovery of new biomarkers. This paper provides an update of novel clinical tests used in research and clinical diagnostic, as well as of potential tissue or fluid biomarkers provided by extensive proteomic research data.

Chandra Gupta S, Nandan Tripathi Y
Potential of long non-coding RNAs in cancer patients: From biomarkers to therapeutic targets.
Int J Cancer. 2017; 140(9):1955-1967 [PubMed] Related Publications
Because of high specificity and easy detection in the tissues, serum, plasma, urine and saliva, interest in exploring the potential of long non-coding RNAs (lncRNAs) in cancer patients continues to increase. LncRNAs have shown potential as a biomarker in the diagnosis and prognosis of bladder cancer, prostate cancer, gastric cancer, pancreatic cancer, breast cancer and many other cancer types. Some lncRNAs have also been used as adjunct to improve the specificity and sensitivity of existing biomarkers. The molecular tools such as RNA-seq, RNA-FISH, ic-SHAPE and quantitative real-time PCR have been used for examining the lncRNAs' potential. Some lncRNAs such as PCA3 is now routinely used in the clinic for the diagnosis of prostate cancer. Single nucleotide polymorphisms (SNPs) in lncRNAs can also be used as a predictor of cancer risk. Although ongoing studies continue to unravel the underlying mechanism, some lncRNAs have been used as therapeutic targets for the selective killing of cancer cells in patients. Thus lncRNAs are emerging as convenient and minimally invasive diagnostic/prognostic markers, and also as therapeutic target. Companies such as the Curna Inc., MiNA Therapeutics Ltd. and RaNA Therapeutics Inc. have been taking steps to develop lncRNA based strategies against cancer. In this review, we discuss the potential of lncRNAs as biomarkers and therapeutic targets in cancer patients.

Filella X, Foj L
Prostate Cancer Detection and Prognosis: From Prostate Specific Antigen (PSA) to Exosomal Biomarkers.
Int J Mol Sci. 2016; 17(11) [PubMed] Free Access to Full Article Related Publications
Prostate specific antigen (PSA) remains the most used biomarker in the management of early prostate cancer (PCa), in spite of the problems related to false positive results and overdiagnosis. New biomarkers have been proposed in recent years with the aim of increasing specificity and distinguishing aggressive from non-aggressive PCa. The emerging role of the prostate health index and the 4Kscore is reviewed in this article. Both are blood-based tests related to the aggressiveness of the tumor, which provide the risk of suffering PCa and avoiding negative biopsies. Furthermore, the use of urine has emerged as a non-invasive way to identify new biomarkers in recent years, including the

Fenstermaker M, Mendhiratta N, Bjurlin MA, et al.
Risk Stratification by Urinary Prostate Cancer Gene 3 Testing Before Magnetic Resonance Imaging-Ultrasound Fusion-targeted Prostate Biopsy Among Men With No History of Biopsy.
Urology. 2017; 99:174-179 [PubMed] Related Publications
OBJECTIVE: To determine whether a combination of prostate cancer gene 3 (PCA3) and magnetic resonance imaging (MRI) suspicion score (mSS) could further optimize detection of prostate cancer on MRI fusion-targeted biopsy (MRF-TB) among men with no history of biopsy.
MATERIALS AND METHODS: We included in this study 187 men presenting to our institution between June 2012 and August 2014 who underwent multiparametric MRI (mpMRI) and PCA3 before MRF-TB. Biopsy results, stratified by biopsy indication and PCA3 score, were recorded. Receiver operating characteristics curves and multivariable logistic regressions were used to model the association of PCA3 and mSS with cancer detection on MRF-TB.
RESULTS: PCA3 is associated with cancer detection on MRF-TB for men with no prior biopsies (area under the curve: 0.67, 95% confidence interval: 0.59-0.76). Using a cutoff of ≥35, PCA3 was associated with cancer risk among men with mSS 2-3 (P = .004), but not among those with mSS 4-5 (P = .340). The interaction of PCA3 and mSS demonstrated significantly higher discrimination for cancer than mSS alone (area under the curve: 0.83 vs 0.79, P = .0434).
CONCLUSION: Urinary PCA3 is associated with mSS and the detection of cancer on MRF-TB for men with no prior biopsies. PCA3 notably demonstrates a high negative predictive value among mSS 2-3. However, in the case of high-suspicion mpMRI, PCA3 is not associated with cancer detection on MRF-TB, adding little to cancer diagnosis. Further studies are needed to evaluate the utility of PCA3 in predicting cancer among men with normal mpMRI.

De Luca S, Passera R, Cattaneo G, et al.
High prostate cancer gene 3 (PCA3) scores are associated with elevated Prostate Imaging Reporting and Data System (PI-RADS) grade and biopsy Gleason score, at magnetic resonance imaging/ultrasonography fusion software-based targeted prostate biopsy after a previous negative standard biopsy.
BJU Int. 2016; 118(5):723-730 [PubMed] Related Publications
OBJECTIVE: To determine the association among prostate cancer gene 3 (PCA3) score, Prostate Imaging Reporting and Data System (PI-RADS) grade and Gleason score, in a cohort of patients with elevated prostate-specific antigen (PSA), undergoing magnetic resonance imaging/ultrasonography fusion software-based targeted prostate biopsy (TBx) after a previous negative randomised 'standard' biopsy (SBx).
PATIENTS AND METHODS: In all, 282 patients who underwent TBx after previous negative SBx and a PCA3 urine assay, were enrolled. The associations between PCA3 score/PI-RADS and PCA3 score/Gleason score were investigated by K-means clustering, a receiver operating characteristic analysis and binary logistic regression.
RESULTS: The PCA3 score difference for the negative vs positive TBx cohorts was highly statistically significant. A 1-unit increase in the PCA3 score was associated to a 2.4% increased risk of having a positive TBx result. A PCA3 score of >80 and a PI-RADS grade of ≥4 were independent predictors of a positive TBx. The association between the PCA3 score and PI-RADS grade was statistically significant (the median PCA3 score for PI-RADS grade groups 3, 4, and 5 was 58, 104, and 146, respectively; P = 0.006). A similar pattern was detected for the relationship between the PCA3 score and Gleason score; an increasing PCA3 score was associated with a worsening Gleason score (median PCA3 score equal to 62, 105, 132, 153, 203, and 322 for Gleason Score 3+4, 4+3, 4+4, 4+5, 5+4, and 5+5, respectively; P < 0.001).
CONCLUSION: TBx improved PCA3 score diagnostic and prognostic performance for prostate cancer. The PCA3 score was directly associated both with biopsy Gleason score and PI-RADS grade: notably, in the 'indeterminate' PI-RADS grade 3 subgroup.

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