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Table 1 Studies investigating cell-free miRNA signatures with diagnostic, prognostic and predictive relevance in prostate cancer

From: Diagnostic, prognostic and predictive value of cell-free miRNAs in prostate cancer: a systematic review

Study design, substrate, and sample size Significant miRNAs Diagnostic value/outcome Reference
TaqMan qRT-PCR analysis of 6 candidate miRNAs in serum from 25 mPC patients and 25 HI. Normalised to spike-ins. miR-141 AUC = 0.907, Sn = 60 %, Sp = 100 % Mitchell et al. 2008 [11]
miRNA profiling by in serum from 6 PC patients (stage 3 and 4) and 8 HI by pan-miRNA microarray. miR-16, miR-34b, miR-92a, miR-92b, miR-103, miR-107, miR-197, miR-328, miR-485-3p, miR-486-5p, miR-574-3p, miR-636, miR-640, miR-766, miR-885-5p Upregulated miRNA levels in PC serum samples Lodes et al. 2009 [118]
qRT-PCR analysis of 3 candidate miRNAs in plasma from 51 PC patients (26 LPC, 25mPC) and 20 HI. Normalized to RNU1A. miR-21, miR-141, miR-221 miR-21: AUC = 0.880 (PC vs HI) Agaoglu et al. 2011 [119]
miR-221: AUC = 0.830 (PC vs HI)
miR-141: AUC = 0.755 (mPC vs LPC)
Discovery: profiling of 667 miRNAs in serum of 7 mPC and 14 LPC patients by TaqMan arrays. Normalised to spike-ins. miR-141, miR-200b, miR-375 69 differentially expressed miRNAs between mPC and LPC. Brase et al. 2011 [120]
Validation 1: analysis of 5 selected miRNA in different PC risk groups (n = 45). Increased miR-375, miR-141, miR-200b levels differentiate pT3 vs pT2, Gleason score 6 vs 7.
Validation 2: analysis of 3 selected miRNA in different PC risk groups (n = 71). miR-375 level differentiate Gleason score 7 vs ≥8 and N0 vs N1/M+
qRT-PCR analysis of 4 candidate miRNAs in serum from 45 PC, 18 BPH patients and 20 HI. Normalised to spike-ins. let-7i, miR-26a, miR-32, miR-195 4 miRNA model: AUC = 0.758, Sn = 78,4 %, Sp = 66.7 % (LPC vs BPH) (PSA AUC = 0.834) Mahn et al. 2011 [121]
Decrease of miR-26a and miR-195 level after prostatectomy
Profiling of 384 miRNAs in serum from 36 PC patients (CAPRA scores: 12 low, 12 medium, 12 high risk) and 12 HI using Fluidigm microfluidic platform, validation of 12 candidate miRNAs by qRT-PCR in the same sample set. miR-24, miR-26b, miR-30c, miR-93, miR-106a, miR-223, miR-451, miR-874, miR-1207-5p, miR-1274a 10 differentially expressed miRNAs (PC vs HI) Moltzhan et al. 2011 [100]
miR-106a, miR-93, miR-1274: a liner relationship between increased miRNA level and increased risk score.
miR-24: a liner relationship between decreased miRNA level and increased risk score.
miR-451: increased in high risk in comparison to low and medium risk PC and HI.
qRT-PCR analysis of miR-21 in serum from 56 patients (20 LPC, 20 ADPC, 10 CRPC and 6 BPH) The 10 CRPC patients received docetaxel-based chemotherapy. miR-21 A liner relationship between increased miR-21 level and increased serum PSA level in patients with ADPC and HRPC. Zhang et al. 2011 [122]
Higher miR-21 levels in patients who were resistant to docetaxel-based chemotherapy.
Profiling of 742 miRNAs in plasma-derived MVs from 78 PC patients (55 LPC, 16 mPC) and 28 HI using Exiqon miRNA qPCR panel. Validation of miR-375 and miR-141 in MV and exosome fractions from sera of 47 mPC and 72 non-recurrent PC patients by TaqMan qRT-PCR. Normalised to spike-ins. 27 differentially expressed miRNAs miR-107, miR-130b, miR-141, miR-181a-2*, miR-2110, miR-301a, miR-326, miR-331-3p, miR-432, miR-574-3p, miRr-625* (PC vs HI). Bryant et al. 2012 [106]
miR-107, miR-141, miR-181a-2*, miR-2110, miR-301a, miR-326, miR-432, miR-574-3p, miR-625* (LPC vs HI).
miR-17*, miR-20a*, miR-23a*, miR-130b, miR-198, miR-200b, miR-375, miR-379, miR-513a-5p, miR-572, miR-577, miR-582-3p, miR-609, miR-619, miR-624*, miR-1236 (mPC vs LPC)
Discovery: profiling of 754 miRNAs in plasma from 25 PC and 17 BPH patients by Illumina miRNA expression platform. Validation: qRT-PCR analysis of 8 selected miRNAs in plasma from 80 PC, 44 BPH and 54 HI. Normalised to U6. let-7c, let-7e, miR-30c, miR-622, miR-1285 5 miRNA model: AUC = 0.860, Sn = 74.1 %, Sp = 83.8 % (PC vs HI) Chen et al. 2012 [96]
AUC = 0.924 (PC vs BPH)
Profiling of 365 miRNAs in serum from 25 mCRPC patients (pooled) and 25 HI (pooled) by TaqMan Low-Density Array. Normalised to spike-ins. Additional testing of individual miRNAs by TaqMan qRT-PCR. miR-141, miR-200a, miR-200c, miR-210, miR-375 Increased miRNA levels in serum samples from mCRPC patients Cheng et al. 2013 [103]
miR-210: correlation with PSA response to treatment
Profiling of 699 miRNAs in serum samples from 28 patients of low-risk LPC and 26 of mCRPC by TaqMan microRNA arrays. miR-141, miR-375, miR-378*, miR-409-3p Increased levels of miR-375, miR-378* and miR-141; decreased level of miR-409-3p (mCRPC vs LPC) Nguyen et al. 2013 [117]
miRNA profiling in the serum of 8 patients with rapid BCR and 8 patients without BCR following RP. Validation: Testing of four candidate miRNAs in 70 independent Gleason 7 PC patient serum samples, 31 of whom had relapse after RP, by qRT-PCR. miR-141, miR-146b-3p, miR-194 Increased miRNA levels in serum samples from patients who had experienced BCR. Selth et al. 2013 [99]
miR-146b-3p (HR = 2.13) and miR-194 (HR = 2.13) were also associated with disease progression in the validation cohort.
qRT-PCR analysis of 4 miRNAs (previously found deregulated in PC tissues) in urine samples from 36 PC patients (GS6 and GS7) and 12 HI. Normalised to RNU48. miR-205, miR-214 Decreased miRNA levels in PC. miR-205: AUC = 0.708, miR-214: AUC = 0.743 Srivastava et al. 2013 [15]
2 miRNA model: Sn = 89 %, Sp = 80 %
Profiling of 742 miRNAs in plasma samples from 25 LPC (pooled) and 25 mCRPC (pooled) patients by Exiqon miRNA qPCR panel. Validation: Analysis of 10 selected candidate miRNAs in 50 individual plasma samples by qRT-PCR. miR-16, miR-141, miR-151-3p 67 differentially expressed miRNAs. Watahiki et al. 2013 [98]
3 miRNA model : AUC = 0.944, Sn = 84 %, Sp = 96 %
Profiling of 732 miRNAs in serum samples from 13 BPH and 31 PC (11 LPC + 9 N1/M1 + 11 CRPC) patients by Exiqon microRNA PCR panel I + II, V2.M. 19 differentially expressed miRNAs miR-562/miR-210/miR-501-3p/miR-375/miR-551b model: AUC = 0.919, Sn = 84 %, Sp = 100 % (BPH vs PC) Haldrup et al. 2014 [97]
miR-375/miR-708/miR-1203/miR-200a model: AUC = 0.875, Sn = 75 %, Sp = 100 % (LPC vs disseminated PC)
let-7a/miR-210/miR-562/miR-616/miR-297 model: AUC = 0.900, Sn = 80 %, Sp = 100 % (BPH vs disseminated PC)
miRNA profiling on docetaxel-resistant and sensitive cell lines to identify candidate circulating miRNA biomarkers and subsequent qRT-PCR analysis of 46 candidate miRNAs in plasma/serum samples collected from 97 CRPC patients before and after docetaxel treatment. miR-20a, miR-20b, miR-21, miR-25, miR-132, miR-146a, miR-200a, miR-200b, miR-200c, miR-201b, miR-222, miR-375, miR-429, miR-590-5p miR-200c/miR-200b/miR-146a/miR-222/miR-201b/miR-20a model for prediction of chemoresponse: AUC = 0.730 Lin et al. 2014 [102]
Pre-docetaxel levels of miR-200b, miR-429, miR-200a, miR-21, miR-200c, miR-590-5p, miR-375, miR-132, miR-20a and post-docetaxel decrease/no-change of miR-20a, miR-222, miR-20b, miR-132 and miR-25 associated with poor overall survival.
miRNA profiling in PSS from 4 BPH patients and 4 PC patients by Agilent miRNA Microarray. miR-133b, miR- 203, miR-221, miR-361-3p 4 miRNA model: AUC = 0.950 Guzel et al. 2015 [14]
Validation: Analysis of 4 candidate miRNA in PSS from 23 PC and 25 BPH patients by qRT-PCR.
Deep sequencing of plasma exosomal RNA in 23 CRPC patients and correlation with OS. Validation: qRT-PCR analysis of candidate miRNAs in a follow-up cohort of 100 CRPC patients. miR-375, miR-1290 miRNA levels significantly associated with poor overall survival. Huang et al. 2015 [107]
Combination of ADT failure time and PSA level at time of CRPC stage with miRNA levels improved predictive performance with AUC increase from 0.660 to 0.730.
qRT-PCR analysis of 12 miRNAs in blood and tissue samples from 75 PC and 27 BPH patients let-7a, miR-141, miR-145, miR-155 4 miRNA model: AUC = 0.783, Sn = 97 %, PPV = 80 % Kelly et al. 2015 [123]
qRT-PCR analysis of 3 candidate miRNAs in cell-free urine fraction from 71 PC patients and 18 HI. miR-483-5p Elevated miRNA levels in PC patients, AUC = 0.694 Korzeniewski et al. 2015 [57]
Discovery: miRNA profiling in cell-free urine from 14 PC and 5 BPH patients. Validation: qRT-PCR analysis of candidate miRNAs in urine in 3 validation cohorts including 593 PC patients and 459 controls. Hsv1-miR-H18, hsv2-miR-H9-5p Hsv1-miR-H18: AUC = 0.772, Sn = 66.5 %, Sp = 74.1 % Yun et al. 2015 [104]
Hsv2-miR-H9-5p: AUC = 0.777, Sn = 70.2 %, Sp = 72.0 %
qRT-PCR analysis of 21 miRNA in serum from 50 low-grade (Gleason grade 3) PC and 50 high grade (Gleason grade 4 + 5) PC. let-7a, miR-24, miR-26b, miR-30c, miR-93, miR-100, miR-103, miR-106a, miR-107, miR-130b, miR-146a, miR-223, miR-451, miR-874 Highly expressed in BPH and low-grade PC, uniformly low levels in high-grade PC. 11 miR model: NPV of 0.939 for prediction of absence of high-grade PC. Mihelich et al. 2015 [101]
  1. ADPC androgen-dependent prostate cancer, BCR biochemical recurrence, BPH benign prostatic hyperplasia, CRPC castration resistant prostate cancer, GS Gleason score, HI healthy individuals, mPC metastatic prostate cancer, LPC localised prostate cancer, MV microvesicle, PC, prostate cancer, PSS prostate secretion samples, qRT-PCR quantitative reverse transcription-polymerase chain reaction, RP radical prostatectomy, Sn sensitivity, Sp specificity. miRNAs identified in more than one study are marked in bold