Table 1 MiRNAs from blood derived products (Serum/Plasma/Blood cells) as brain tumor biomarkers

miR-21

↑

Wang, 2012 [100]

Plasma

30 Glioma

Distinguishes between GBM and healthy controls

Glioma vs. healthy controls

qRT-PCR

(10 Gr II)

Expression levels cannot distinguish between glioma grades

AUC = 0.9300 (95% CI: 0.7940–1.066)

(10 Gr III)

Cannot distinguish between glioma and other brain tumors

SS = 90.0%

(10 Gr IV)

SP = 100%

10 Meningioma

10 Hyphophysoma

10 Healthy controls

miR-29

↓

Wu, 2015 [106]

Serum

83 Glioma

Distinguishes HGG^a from healthy controls

AUC = 0.81 (95% CI, 0.73–0.89).

qRT-PCR

(36 Gr I-II)

Not a brain cancer specific marker

(47 Gr III-IV)

69 Healthy controls

miR-21

↑

D’Urso, 2015 [101]

Blood

30 Glioma

Combined diagnostic tree using miR-15b and miR-21 can distinguish glioma from other conditions

Combined miR-15b and mir21

miR-15b

↑

Microarray

(8 Gr II)

SS = 90%

miR-16

↓

qRT-PCR

(6 Gr III)

Mir-16 levels could distinguish between grades of Glioma (lowest expression in GBM)

SP = 100%

(16 Gr IV)

miR-16 to distinguish between Gr IV and II/III

30 Various neurological

AUC = 0.98

disorders

SS = 0.98%

36 PCNSL^c

SP = 99%

16 Secondary brain

metastases

miR-21

↑

Santangelo, 2018

Serum

100 Glioma

Higher serum levels of 3 miRNA panel in GBM and HGG compared to LGG^b and healthy controls

Cumulative 3 miRNA panel; GBM vs healthy:

miR-222

↑

[102]

Exosomes

(2 Gr I)

Cumulative 3 miRNA panel distinguishes between GBM, HGG, LGG and healthy controls

AUC = 0.87 (95% CI 0.7885–0.9524, p < 0.0001)

miR-124-3p

↑

qRT-PCR

(13 Gr II)

High serum levels return to normal postoperatively

SS = 84%

(16 Gr III)

SP = 77%

(69 Gr IV)

*For HGG, LGG, Metastases vs healthy control, see original article

11 Brain metastases

30 Healthy controls

miR-203

↓

Chen, 2017 [107]

Serum

70 GBM^d

Distinguishes between GBM and LGG, GBM and healthy controls

GBM vs LGG

qRT-PCR

30 LGG

Lower serum level correlated with larger tumor size, lower KPS^e score, lower OS^f and lower PFS^g

AUC = 0.814

30 Healthy controls

GBM vs healthy controls

AUC = 0.862

miR-137

↓

Li, 2016 [108]

Serum

64 glioma

Downregulated levels in glioma compared to controls

NA

qRT-PCR

(35 Gr I/II)

Further downregulation in HGG

(29 Gr III/IV)

64 Controls

Low levels associated with lower OS of glioma patients

miR-185

↓

Tang, 2015 [103]

Serum

66 Glioma

Downregulation of mir-185 specifically associated with glioma patients compared to oncologic non-glioma patients

NA

qRT-PCR

(23-Gr I + II)

Lower serum mir-185 levels in Grade III-IV glioma compared to Grade I-II

(43-Gr III + IV)

Lower mir-185 levels correlated with lower OS

11 Pituitary adenoma

Up-regulation of mir-185 levels after chemoradiation

32 Meningioma

14 Acoustic neuroma

miR-210

↑

Lai, 2015 [109]

Serum

136 Glioma

Upregulation of mir-210 can distinguish glioma from healthy controls

Overall glioma (Gr I-IV) vs healthy controls

qRT-PCR

(13 Gr I)

miR-210 levels associated with tumor grade

AUC value of 0.927 (95% CI1/40.889–0.964)

(35 Gr II)

(Upregulation trend in glioma Gr I-II vs healthy controls; Statistical significant upregulation in Gr III-IV vs healthy controls)

NPV = 72.5%

(46 Gr III)

High mir-210 levels associated with lower OS

PPV = 91.3%

(32 Gr IV)

SS = 91.27%

50 Healthy controls

SP = 72.50%

miR-205

↓

Yue, 2016 [104]

Serum

64 Glioma

Significant downregulation of mir-205 in all grades glioma compared to healthy controls

Overall glioma (Gr I-IV) vs healthy controls

qRT-PCR

(7 Gr I)

Stepwise decrease in serum mir-205 levels with ascending pathological grades

AUC = 0.935

(9 Gr II)

Significantly lower mir-205 levels in glioma versus other brain-tumors

PPV = 96.4%,

(21 Gr III)

Downregulation of mir-205 correlated with KPS score and OS

NPV = 65.8%,

(27 Gr IV)

SS = 86.3%,

45 Healthy controls

SP = 92.2%,

8 Meningioma

6 PCNSL

5 Pituitary adenoma

miR-221/222 Family

↑

Zhang, 2016 [110]

Serum

50 Glioma

Distinguishes glioma from healthy controls

miR-221:

qRT-PCR

51 Healthy controls

AUC = 0.84 (95% CI: 0.74–0.93)

miR-222:

AUC = 0.92 (95% CI 0.87–0.94)

miR-301a

↑

Lan, 2018 [105]

Serum exosomes

60 Glioma

Higher levels in glioma vs controls

NA

qRT-PCR

43 Heallthy controls

Higher levels in glioma vs other types of cancers

9 Meningioma

Higher levels correlated with ascending pathological grades and lower KPS

7 PCNSL

Levels decrease postoperatively

10 Pituitary adenoma

Secondary increase may reflect local recurrence

Serum levels in HGG are independently associated with longer OS

miR-397a

↓

Huang, 2017 [113]

Serum

100 Glioma

Distinguishes glioma from healthy controls

miR-376a: AUC = 0.872; SS = 81.0%; SP = 82.0%

miR-397b

↓

miR-397c

↓

qRT-PCR

(10 Gr I)

Decreased levels associated with advanced WHO grade and low KPS

miR-376b: AUC = 0.890; SS = 82.0% SP = 78.0%;

(20 Gr II)

Higher miRNA levels associated with better OS

miR-376c: AUC = 0.837; SS = 90.0%; SP = 70.0%

(30 Gr III)

(40 Gr IV)

150 Healthy controls

miR-122

↓

Tang, 2017 [114]

Plasma

74 Glioma

Distinguishes between glioma and healthy controls

AUC = 0.939

qRT-PCR

(14 Gr I)

Further downregulation of serum levels in higher grade gliomas

SS = 91.9%

(17 Gr II)

The miRNA level is an independent prognostic factor for OS

SP = 81.1%

(20 Gr III)

(23 Gr IV)

74 Healthy controls

miR-125b

↓

Regazzo, 2016 [112]

Serum

22 Glioma

Distinguishes between GBM and lower grade (II/III) gliomas

miR-125b: GBM vs lower grade glioma, AUC = 0.75 (95%

miR-497

↓

qRT-PCR

(12 Gr II/III)

CI = 0.533–0.967)

(10 Gr IV)

miR-497: GBM vs lower grade glioma, AUC = 0.87 (95%

8 Meningioma

confidence interval (CI) = 0.712–1

15 Healthy controls

miR-125b

↓

Wei, 2016 [111]

Serum

33 Glioma

Distinguishes between glioma and healthy controls

Glioma vs healthy controls

qRT-PCR

(11 Gr I)

AUC = 0.839 (95% CI: 0.743–0.935)

(11 Gr II)

(11 Gr III/IV)

33 Healthy controls

miR-182

↑

Xiao, 2016 [115]

Serum

112 Glioma

Distinguishes between glioma and healthy controls

Glioma vs healthy controls

qRT-PCR

(18 Gr I)

The expression levels associated with KPS score and WHO grade and correlated with lower OS and DFS,

AUC = 0.778

(23 Gr II)

The level is independent prognostic factor for OS

SS = 58.5%

(32 Gr II)

SP = 85.2%

(39 Gr IV)

54 Healthy controls

miR-128

↓

Sun, 2015 [121]

Serum

151 Glioma

Distinguishes between glioma and healthy controls and meningioma

Glioma vs healthy controls

qRT-PCR

(24 Gr I)

Distinguishes Gr II-IV from Gr I

AUC = 0.9095

(23 Gr II)

Levels elevated after surgery and correlate with the pathological grade and KPS

Glioma vs Meningioma

(43 Gr III)

AUC = 0.8283

(61 Gr IV)

Glioma II-IV vs I

59 Post-op glioma

AUC = 0.7362

52 Meningioma

53 Healthy controls

30 Glioma

miR-128

↓

Wang, 2012 [100]

Plasma

(10 Gr II)

Can distinguish between GBM and healthy controls

AUC (miR-128 or miR-342-3p) = 1.000 (95% CI: 1.000–1.000)

miR-342-3p

↓

qRT-PCR

(10 Gr III)

Decreased levels correlated with glioma grade

SS = 90.0%

(10 Gr IV)

Significant upregulation after operation and chemoradiation

SP = 100%

10 meningioma

10 Hyphophysoma

10 Healthy controls

miR-128

↑

Roth, 2011 [120]

Blood cells

20 Glioblastoma

Distinguishes between GBM and healthy controls

GBM vs healthy controls

miR-342-3p

↓

Microarray

20 Healthy Controls

Authors apply statistic learning techniques (SVM = Support vector machines) and compute the diagnostic accuracy of miRNA profiles; a 180 miRNA signature calculated to have the highest diagnostic accuracy in distinguishing GBM from healthy controls.

miR-128:

qRT-PCR

AUC = 0.828

miR-342-3p

AUC = 0.18

180 miRNA signature:

SS = 83%

SP = 79%

RNU6–1

↑

Manterola, 2014

Serum exosomes

Initial screening

3 small non coding RNAs can distinguish between GBM and healthy controls

RNU6–1

miR-320

↑

[119]

Low density array

25 Glioblastoma

(machine learning algorithm)

AUC = 0.852 (95% CI, 0.74–0.96)

miR-574-3p

↑

qRT-PCR

25 Healthy controls

SS = 73%; SP = 70%

Confirmation

Results from initial screening not confirmed is the second study group, only RNU6–1 was found significantly up-regulated!

miR-320

50 Glioblastoma

AUC = 0.720

30 Healthy controls

(95% CI, 0.56–0.87)

SS = 65%; SP = 65%

miR-574-3p

AUC = 0.738 (95% CI, 0.58–0.89)

SS = 59%; SP = 59%

3 sncRNA signature:

AUC = 0.926 (95%[CI], 0.84–1)

SS = 87%; SP = 86%

miR-454-3p

↑

Shao, 2015 [117]

Plasma

70 Glioma

Distinguishes between glioma and healthy controls

Glioma vs healthy controls

qRT-PCR

(8 Gr I)

Higher levels in higher WHO grades and the levels decrease significantly postoperatively

AUC = 0.9063 [95% (CI): 0.8487–0.9639)]

(15 Gr II)

Weak correlation between high levels and OS

SS = 99.05%

(25 Gr III)

SP = 82.86%

(22 Gr IV)

70 Healthy controls

miR-451a

↓

Zhao, 2016 [116]

Serum

118 Glioma

Distinguishes between glioma and healthy controls

Glioma vs healthy controls

qRT-PCR

(27 Gr I)

Levels return to almost healthy control expression 7 days after surgery

AUC = 0.816

(33 Gr II)

The expression level downregulation correlates with WHO grade and KPS

SS = 81.4%

(33 Gr III)

SP = 79.7%

(25 Gr IV)

84 Healthy controls

miR-15b-5p

↓

Yang, 2013 [122]

Serum

148 Glioma

Significantly decreased in glioma (Gr I-IV) compared to healthy controls

SS = 88.00%

miR-23a

↓

miR-133a

↓

miR-150*

↓

miR-197

↓

Solexa sequencing

(15 Gr I)

Malignant astrocytoma prediction

SP = 97.87%

miR- 497

↓

miR-548b-5p

↓

qRT-PCR

(55 Gr II)

Significant postoperative upregulation of aforementioned miRNAs

(45 Gr III)

(33 Gr IV)

11 Astrogliosis

80 Healthy controls

miR-15b-5p

↑

Zhi, 2015 [123]

Serum

90 Glioma

Combined 9 miRNA panel distinguishes glioma from healthy controls

AUC = 0.9722 (95% CI, 0.9501–0.9942)

miR-16-5p

↑

miR-19a-3p

↑

miR-19b-3p

↑

miR-20a-5p

↑

TaqMan

(28 Gr II)

Levels decrease postoperatively

SS = 93.3%

miR-106a-5p

↑

miR-130a-3p

↑

Low density Array

(38 Gr III)

miR-20a-5p, miR-106a-5p, and miR-181b-5p associated with advanced glioma stages

SP = 94.5%

miR-181b-5p

↑

miR-208a-3p

↑

qRT-PCR

(24 Gr IV)

miR-19a-3p, miR-106a-5p, and miR-181b-5p significantly associated lower OS.

110 Healthy controls

miR-17

↑

Xu, 2017 [118]

Serum

47 Glioma

Distinguishes between glioma and healthy controls

miR-17;

AUC = 0.787 [95% (CI): 0.690–0.865)]

SS = 89.3%; SP = 55.3%

miR-130a

AUC = 0.720 [95% (CI): 0.617–0.807)]

SS = 70%; SP = 65.2%

miR-10b

AUC = 0.721 [95% (CI): 0.619–0.808)]

SS = 44.6%; SP = 93.6%

miR-Score (all three miRNA)

AUC = 0.872 [95% (CI): 0.787–0.932)]

SS = 72.3%; SP = 85.1%

miR-130a

↑

qRT-PCR

(16 Gr I-II)

Higher serum levels in HGG compared to LGG

miR-10b

↑

(31 Gr III-IV)

45 Healthy controls

miR-93

↑

Goze, 2018 [124]

Whole blood

15 DLGG^h

3 miRNA signature tree distinguishes DLGG from healthy controls

miRNA-93; AUC = 0.83556

miR-590-3p

↑

miR-454

↑

TaqMan OpenArray RT-qPCR platform

15 Healthy controls

miRNA-590-3p; AUC = 0.8133

miRNA-454; AUC = 0.75111