MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia: Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
3. Results
3.1. miRNA Polymorphisms and Childhood ALL
Study | Cohort Characteristics | Methods | Outcomes |
---|---|---|---|
Siyadat et al., 2021 [92] | 100 childhood B-ALL patients and 105 controls; Iran | RT-PCR, HRM and Sanger sequencing; BM or whole blood | No significant relationship was confirmed between rs12803915 variants of miR-612 and susceptibility to B-ALL. |
Pei et al., 2020 [90] | 266 childhood ALL patients and 266 controls; Taiwan | PCR-RFLP; whole blood | The G allele of miR-146a polymorphism rs2910164 seems to be a protective biomarker for childhood ALL (OR, 0.66; 95% CI: 0.52 to 0.85; p = 0.0011), whereas patients with the GG genotype were associated with decreased susceptibility to ALL (OR, 0.4; 95% CI: 0.23 to 0.67; p = 0.0004) compared with healthy controls. Conspicuously, children bearing CG and GG genotypes were found to have earlier onset compared to those with CC genotype (p = 0.025 and p = 0.0001, respectively). The G>C polymorphism leads to reduced amounts of mature miR-146a, whereas the C allele has reduced capacity to inhibit target genes. |
C.C. Chen et al., 2020 [93] | 266 childhood ALL patients and 266 controls; Taiwan | PCR-RFLP; whole blood | The T>C polymorphism of rs11614913 in miR-196a-2 does not seem to be associated with susceptibility to childhood ALL. |
De Souza et al., 2020 [88] | 100 childhood B-ALL patients and 180 adult controls; Brazil | qRT-PCR; whole blood | The mutant homozygote (AA) genotype of DROSHA rs3805500 was associated with a threefold increase in the risk of developing ALL (recessive model: GG + GA vs. AA; OR, 2.913; 95% CI: 1.415 to 5.998; p = 0.004). The mutant homozygote (GG) genotype of the miR-499 gene rs3746444 was associated with a 17.8-fold increase in the risk of developing ALL (recessive model: AA + AG vs. GG; 95% CI: 5.55 to 57.016; p < 0.001). In contrast, the wild homozygous (CC) genotype of the miR-938 gene rs2505901 seems to confer a protective effect against developing ALL (dominant model: CC vs. CT + TT; OR, 0.359; 95% CI: 0.160 to 0.805; p = 0.013). No significant associations for AGO1 rs636832, MIR219A1 rs213210 and rs107822, MIR146A rs2910164, MIR330 rs12894467 and MIR608 rs4919510. |
Jemimah Devanandan et al., 2019 [47] | 71 childhood ALL patients and 74 controls; India | qRT-PCR; whole blood | No statistically significant association was found between miR-146a gene SNPs rs2910164 G>C and rs57095329 A>G and ALL risk. |
Xue et al., 2019 [42] | 831 childhood ALL patients and 1079 controls; validation: 88 childhood ALL cases and 99 controls; China | qRT-PCR; whole blood; plasma from validation cohort | Subjects carrying the mutant homozygous TT genotype of miR-100 rs543412 had a statistically significantly decreased risk of childhood ALL (OR, 0.73; 95% CI: 0.55 to 0.97; p = 0.029). No association was been found for miR-146a rs2910164 and miR-210 rs7395206 polymorphisms and ALL. |
Gutierrez-Camino et al., 2018 [94] | 217 children with B-ALL and 330 controls from Spain and 75 children with B-ALL and 96 controls from Slovenia | GoldenGate genotyping assay and OpenArray genotyping; whole blood or BM | The AA genotype of rs12402181 in miR-3117-3p was associated with B-ALL risk (OR, 1.44; 95% CI: 1.01 to 2.08; p = 0.047; GG vs. AG vs. AA) in the Spanish cohort. The same effect was observed in the Slovenian cohort (OR, 2.01; 95% CI: 1.02 to 3.95; p = 0.041). When both populations were analyzed together, they displayed a more significant trend (OR, 1.53; 95% CI: 1.12 to 2.09; p = 0.006). With respect to allele frequency analysis, minor allele A showed a 1.51-fold increased risk of B-ALL in total (95% CI: 1.11 to 2.05; p = 0.007). The CT/CC genotype in rs62571442 of miR-3689d-2 was associated with a significantly increased risk of developing B-ALL (OR, 1.48; 95% CI: 1.02 to 2.15; p = 0.039) in the Spanish cohort, whereas the risk was even greater in the Slovenian cohort (OR, 3.57; 95% CI: 1.57 to 8.12; p = 0.001). Analyzed together, both cohorts confirmed the latter association (OR, 1.31; 95% CI: 1.06 to 1.60; p = 0.011). Allele frequency analysis in both populations showed that minor allele C is associated with a 1.31-fold increased risk of B-ALL (95% CI: 1.06 to 1.6; p = 0.012). |
Liu et al., 2018 [95] | 200 childhood ALL patients and 100 controls; China | RFLP; whole blood | The miR-146a rs2910164 CC or CG genotype significantly increased the risk of ALL (frequency of GG, GC and CC genotypes in the patient group and in the control group was 16%, 44.5%, 39.5%, and 29%, 41%, 30%, respectively). The expression of GC/CC genotypes were significantly higher in patients than in controls (GG genotype as reference; for the GC genotype: OR, 1.967; 95% CI: 1.054 to 3.672; p = 0.037; and for the CC genotype: OR, 2.386; 95%CI: 1.239 to 4.595; p = 0.012). |
Rakmanee et al., 2017 [96] | 104 childhood ALL patients and 180 controls; Thailand | PCR-RFLP; whole blood | Variant CC of rs11614913 in miR-196a-2 (OR, 4.321; 95% CI: 2.091 to 8.930; p < 0.001), TC heterozygote (OR, 2.248; 95% CI: 1.103 to 4.579; p = 0.024) and CC+TC genotypes (OR, 2.921; 95% CI: 1.504 to 5.673; p = 0.001) were associated with childhood ALL susceptibility compared with the TT wild type. CC homozygotes were associated with significantly increased miR-196a-2 expression. |
Chansing et al., 2016 [97] | 100 childhood ALL patients and 200 controls; Thailand | PCR-RFLP; whole blood | There was no association between miR-146a rs2910164 G>C polymorphism and susceptibility to childhood ALL. |
Hashemi et al., 2016 [98] | 110 childhood ALL patients and 120 controls; Iran | PCR-RFLP; whole blood | A study of polymorphism rs4938723 in pri-miR-34b/c in ALL and healthy children revealed decreased risk of ALL in heterozygous (OR, 0.48; 95% CI: 0.28 to 0.84; p = 0.012; TC vs. TT), and overdominant (OR, 0.51; 95% CI: 0.3 to 0.89; p = 0.02; TC vs. TT+CC) inheritance models. The C allele significantly decreased the risk of childhood ALL compared to the T allele (OR, 0.52; 95% CI: 0.33 to 0.83; p = 0.006). |
Tong et al., 2016 [99] | 570 childhood ALL patients at diagnosis and 673 controls; China | RT-PCR; whole blood | The CC genotype in rs4938723 of pri-miR-34b/c was associated with significantly reduced ALL risk (CC vs. TT: OR, 0.51; 95% CI: 0.33 to 0.8; p = 0.003, and CC vs. TT+TC: OR, 0.49; 95% CI: 0.32 to 0.75; p = 0.002). |
Gutierrez-Camino et al., 2014 [91] | 213 childhood precursor B-ALL patients and 387 adult controls; Spain | OpenArray; remission BM or whole blood | The A allele of rs12803915 in premature mir-612 was found to be protective (GG vs. GA vs. AA; OR, 0.61; 95% CI: 0.42 to 0.88; p = 0.007) against ALL risk. The G allele of rs3746444 in the seed region of mature miR-499-3p was also found to be protective (AA vs. AG vs. GG; OR, 0.67; 95% CI: 0.49 to 0.91; p = 0.009). An association with rs10061133 in mir-449b was also identified (AA vs. GA+GG; OR, 0.52; 95% CI: 0.31 to 0.89; p = 0.012). Eight SNPs present in the six miRNA biogenesis pathway genes (TNRC6B, DROSHA, DGCR8, EIF2C1 or AGO1, CNOT1 and CNOT6) were also identified. |
Hasani et al., 2014 [89] | 75 childhood ALL patients and 115 controls; Iran | T-ARMS-PCR; whole blood | The G>C variant of rs2910164 in hsa-miR-146a was found to significantly increase risk of ALL (CC vs. GG; OR, 4.24; 95% CI: 1.52 to 11.87; p = 0.006, and GC vs. GG; OR, 3.55; 95% CI: 1.41 to 8.93; p = 0.007; C vs. G; OR 1.73; 95% CI: 1.13 to 2.67; p = 0.012). No association was found between rs3746444 of miR-499 and ALL risk. |
3.2. Downregulated miRNAs
3.2.1. miR-125b
3.2.2. miR-142
3.2.3. miR-196b
3.2.4. miR-223
3.2.5. Other Downregulated miRNAs
3.3. Upregulated miRNAs
3.3.1. miR-128 Family
3.3.2. miR-155
3.3.3. miR-181 Family
3.3.4. miR-708
3.3.5. Other Upregulated miRNAs
3.4. miRNAs and ALL Subtypes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Study | Cohort Characteristics | Methods | Outcomes |
---|---|---|---|
Sun et al., 2021 [25] | 43 childhood ALL patients and 14 controls; validation: 28 childhood ALL patients and 28 controls; China | qRT-PCR and microarray; BM | Significant upregulation of miR-155-5p in ALL samples compared with controls (p < 0.05). |
Zamani et al., 2021 [26] | 59 children with ALL at diagnosis and 50 non-cancer controls; Iran | qRT-PCR; BM | Significantly lower miR-324-3p and miR-508-5p expression in children with ALL (p < 0.0001 and p < 0.005, respectively). ROC analysis evaluated the utilization of miR-324-3p (AUC = 0.73; sensitivity, 44% (95% CI: 29.99 to 58.75); specificity, 100% (95% CI: 92.75 to 100); cutoff value, 0.9506; p < 0.0001) and miR-508-5p (AUC = 0.664; sensitivity, 40%; 95% CI: 26.41 to 54.82; specificity, 95.92%; 95% CI: 86.02 to 99.5; cutoff value, 0.1812; p = 0.005) as potential diagnostic biomarkers in pediatric ALL. |
Liang et al., 2021 [27] | 42 childhood ALL patients at diagnosis and controls from GEO databases GSE56489 (43 children with ALL and 14 controls) [28] and GSE23024 (81 children with ALL and 7 controls) [29]; China | qRT-PCR and microarray; BM | Differentially expressed miR-155 and miR-199b were documented in all three datasets. Analysis of datasets showed several other differentially expressed miRNAs. With respect to the GSE56489 dataset, significant differential expression of miR-606, miR-640, miR-199b-3p, miR-145, miR-297, miR-181a*, miR-1322, miR-155, miR-146a, miR-587, miR-1323, let-7b*, miR-548i, miR-3121, miR-449a, miR-369-3p, miR-708 and miR-181b was observed in ALL patients compared to controls (p < 0.05). With respect to the GSE23024 dataset, significant differential expression of miR-199b, miR-432, miR-224, miR-376a, miR-148a, miR-485-3p, miR-411, miR-382, miR-503, miR-223, miR-199a, miR-450, miR-338, miR-424, miR-145, miR-143, miR-618, miR-128b, miR-363, miR-497, miR-153, miR-659, miR-34a, miR-181b, miR-181d, miR-181c, miR-130a, miR-210, miR-130b, miR-579 and miR-155 was observed in children with ALL compared with healthy children (p < 0.05). |
El-maadawy et al., 2021 [30] | 43 childhood ALL patients and 42 controls; Egypt | qRT-PCR; PBMCs | Significant elevation in miR-21 (p < 0.05), miR-148a (p < 0.01) and miR-24 (p < 0.05) expression levels in ALL patients compared to controls. No significant change in miR-26a and miR-133b levels. ROC curve analysis demonstrated the highest AUC for miR-24, followed by miR148a and miR-133b (0.785, 0.719 and 0.669, respectively). No significant results with respect to miR-21 and miR-26 ROC curves. At a cutoff value of 2.928, miR-24 showed 72% sensitivity and 81% specificity (p < 0.001) in detecting ALL cases. Compared to healthy subjects, ALL patients showed a positive correlation between miR-148a and miR-24 (r = 0.347; p < 0.05). Another positive correlation was found between miR-26a and miR-24 (r = 0.353; p < 0.05) in the ALL group compared to the control group. |
Zhu et al., 2021 [31] | 132 childhood ALL patients and 80 controls; China | qRT-PCR; serum | Significantly higher expression levels of serum miR-922 and miR-506 in children with ALL than controls (p < 0.001). ROC curve analysis reported optimal cutoff values of miR-922 and miR-506 for the diagnosis of childhood ALL of 1.46 and 2.17, respectively. |
Fayed et al., 2021 [32] | 71 childhood ALL patients (32 newly diagnosed, 21 relapsed and 18 remitted) and 30 controls; Egypt | qRT-PCR; plasma | AUC of miR-92a (0.755; cutoff 8.77) with 41.5% sensitivity and 100% specificity, whereas miR-638 showed an AUC of 0.862 and sensitivity and specificity of 54.7% and 100%, respectively (cutoff, 6.79). Levels of miR-92a and miR-638, as well as the miR-92a/miR-638 ratio, were significantly higher (17.89, 10.19 and 1.75-fold, respectively) in children newly diagnosed with ALL compared to controls. There was a significant positive correlation of miR-92a and miR-638 levels in children with ALL (r = 0.955; p ˂ 0.0001). |
Li Shao-Wu et al., 2020 [33] | 130 newly diagnosed children with T-ALL and 50 controls; China | qRT-PCR; PBMCs | Expression of miR-146a and miR-221 in T-ALL subjects was significantly higher than in controls (5.83 ± 1.54 vs. 0.96 ± 0.17 and 7.13 ± 2.6 vs. 1.64 ± 0.51, respectively; p < 0.01). Diagnostic cutoff values of miR-146a and miR-221 in childhood T-ALL were determined to be 3.9 and 5.28, respectively, by means of ROC curve analysis. The AUC of T-ALL jointly diagnosed by miR-146a and miR-221 was 0.835 (95% CI: 0.764 to 0.892) with high sensitivity (85%) and specificity (77.2%). In addition, levels of miR-146a were positively correlated with miR-221 levels at diagnosis (r = 0.784, p < 0.01). |
Li Chunyu et al., 2020 [34] | 59 childhood ALL patients at diagnosis and 30 controls; China | qRT-PCR; BM | Expression of miR-223 was markedly reduced in patients with ALL compared with controls (p < 0.001). The ROC curve confirmed the diagnostic value of miR-223 in ALL: AUC, 0.978 ± 0.013; sensitivity, 93.22%; and specificity, 93.33% (cutoff, 0.705; p < 0.0001). miR-223 seems to inhibit cell proliferation, migration and invasion and to promote apoptosis by targeting FOXO1 (which was upregulated in ALL patients). |
Shafik et al., 2020 [35] | 70 childhood ALL patients at diagnosis and 7 controls; Egypt | qRT-PCR; BM | The expression of miR-181a was statistically significantly elevated in ALL patients compared to controls (p < 0.001). However, miR-196b expression was significantly downregulated in ALL patients compared to controls (p = 0.038). High expression of miR-181a was reported in 68 out of 70 ALL patients (97.1%; cutoff, 0.015), whereas 49 of 56 children with ALL (87.5%; cutoff, 0.001) were found to exhibit low miR-196b expression. A significant positive correlation was observed between miR-181a and miR-196b expression levels (r = 0.344; p = 0.009). |
Akpinar et al., 2020 [36] | 13 childhood ALL patients at diagnosis and 5 controls; Turkey | qRT-PCR; whole blood | Significant downregulation of miR-375 and upregulation of miR-21, miR-222, miR-30, miR-145, miR-146a and miR-155 levels in ALL patients compared with controls. |
Chen et al., 2020 [37] | 42 childhood T-ALL patients (21 primary and 21 recurrent) and 20 controls; China | qRT-PCR; PBMCs | Significant downregulation of miR-335-3p in T-ALL patients compared with controls (p < 0.05). |
N. Hassan et al., 2020 [38] | 85 childhood ALL patients at diagnosis and 12 controls; Egypt | qRT-PCR; BM | Expression of miR-100 was significantly downregulated in ALL patients compared to controls (p = 0.035). Expression of miR-210 was significantly upregulated in ALL patients compared to controls (p = 0.025). ROC curve analysis revealed an AUC 0.642 for miR-100 (95% CI: 0.519 to 0.764; cutoff, 2.6; 64.7% sensitivity and 62.5% specificity), whereas the AUC for miR-210 was 0.65 (95% CI: 0.511 to 0.79; cutoff, 3.5; 60% sensitivity and 58.3% specificity). |
S.S. Hassan et al., 2020 [39] | 60 childhood ALL patients (30 HCV and 30 non-HCV) at diagnosis, 10 controls with HCV and 2 healthy controls; Egypt | qRT-PCR; PBMCs | Hepatitis C virus genotype 4 (HCV-4)-associated ALL cases displayed a 3-fold increase in the expression of miR-155 compared to children with chronic HCV infection (47.8 vs. 16.2), suggesting it as a therapeutic target in the respective cases. In addition, ALL patients seemed to express higher levels of miR-155, regardless of whether they were HCV-infected or not. |
Al Nakeeb et al., 2020 [40] | 20 childhood ALL patients and 30 controls; Iraq | qRT-PCR; serum | Expression levels of miR-142-3p and miR-146a-3p were significantly downregulated, whereas miR-223-3p expression was significantly upregulated in ALL patients compared with healthy children. |
Dawidowska et al., 2019 [10] | 34 childhood T-ALL patients and 5 controls; Poland | RNA-seq and qRT-PCR; BM | Significant overexpression of miR-548a-3p, miR-128-3p, miR-181b-5p, miR-20b-5p, miR-6500-3p, miR-331-5p, miR-363-3p, miR-153-3p, miR-466 and miR-130a-3p (p < 0.01; also miR-20b-3p, miR-210-3p, miR-181a-3p, miR-4421, miR-18b-5p, miR-181a-2-3p, miR-181a-5p, miR-625-3p, miR-130b-3p, miR-4687-5p, miR-4437, miR-625-5p and miR-3609 with 0.01 ≤ p < 0.05) in T-ALL samples compared with controls. Significantly lower levels of miR-574-5p, miR-10a-5p, miR-582-3p, miR-143-3p, miR-941, miR-145-5p, miR-27a-5p, miR-618, miR-24-2-3p, miR-145-3p, miR-504-5p, miR-3690, miR-223-5p, miR-199b-5p, miR-550a-5p, miR-4695-3p, miR-30a-5p, miR-3909, miR-2115-3p, miR-582-5p, miR-504-3p, miR-23a-5p, miR-10b-5p, miR-4494 and miR-151a-3p (p < 0.01; also miR-223-3p, miR-6865-3p, miR-7849-3p, miR-1275, miR-338-5p, miR-3150b-5p, miR-3154, miR-6823-5p, miR-10a-3p, miR-143-5p and miR-4745-3p with 0.01 < p < 0.05) in T-ALL samples compared with controls. |
Sheybani et al., 2019 [41] | 27 childhood B-ALL patients (non-Ph-positive; 19 at diagnosis and 8 at relapse) and 16 controls; Iran | qRT-PCR; BM | Significant downregulation of miR-326 was noted in B-ALL patients compared with controls. |
Xue et al., 2019 [42] | 831 childhood ALL patients and 1079 controls; validation: 88 childhood ALL cases and 99 controls; China | qRT-PCR; whole blood; plasma from validation cohort | Expression levels of miR-100 in plasma of childhood ALL cases were 3.25-fold higher than in controls (p < 0.001). |
Pouyanrad et al., 2019 [43] | 64 childhood ALL patients (46 at diagnosis and 18 at relapse) and 30 controls; Iran | qRT-PCR; BM | Expression of miR-335-3p was found to be significantly downregulated in children with ALL compared with controls (0.33 ± 0.04 vs. 0.7325 ± 0.13; p = 0.005). Moreover, miR-335-3p was noticeably downregulated in relapsed patients (0.08 ± 0.02) compared with controls (0.73 ± 0.13; p = 0.0002), and miR-335-3p levels were also lower in newly diagnosed ALL patients compared with controls (p = 0.018). |
El-Khazragy et al., 2019a [44] | 45 childhood ALL patients and 10 controls; Egypt | qRT-PCR; BM | Expression levels of miR-155 and miR-181a were significantly higher in ALL patients compared to controls (p < 0.01). |
El-Khazragy et al., 2019b [45] | 120 childhood ALL patients at diagnosis and 30 controls; Egypt | qRT-PCR; PBMCs and BM | Pediatric ALL samples exhibited significantly lower expression of miR-125b (p < 0.001) compared with controls. In contrast, Bcl-2 expression levels were significantly higher in ALL patients compared with controls (p < 0.001). ROC curve analysis illustrated that miR-125b and Bcl-2 expression could be potential biomarkers for discrimination children with ALL from healthy control, with an AUC 0.99, 0.9 reciprocally. However, miR-125b was superior to Bcl-2: miR-125b sensitivity 98.3% and specificity 96.7% (cutoff ≤ 1.5); Bcl-2 sensitivity 96.6% and specificity 70% (cutoff > 2.14). |
Rzepiel et al., 2019 [46] | 20 childhood BCP-ALL patients (15 at diagnosis and 5 at relapse) and 10 controls; Hungary | qRT-PCR and TLDA; plasma and BM | Various circulating miRNAs in plasma displayed significantly different expressions between BCP-ALL patients and controls: upregulation of miR-34a-5p, miR-128-3p, miR-146a-5p, miR-155-5p, miR-181a-5p, miR-181b-5p, miR-181c-5p, miR-222-3p, miR-532-5p (p < 0.001), miR-21-5p, miR-92a-3p, miR-125b-5p, miR-320a, miR-361-3p, miR-660-5p (p < 0.01), miR-16, miR-30d-5p and miR-93-5p (p < 0.05); downregulation of miR-223-3p, miR-494-3p (p < 0.001) and miR-374a-5p (p < 0.05). There was no significant correlation between miR expression levels in bone marrow and peripheral blood. |
Jemimah Devanandan et al., 2019 [47] | 71 childhood ALL patients and 74 controls; India | qRT-PCR; whole blood | Downregulation of miR-146a in ALL patients compared to controls, although not significant. |
Wang et al., 2019 [48] | 28 childhood ALL patients and 10 controls; China | qRT-PCR; BM | The mRNA expression of miR-146a was significantly increased in children with ALL compared with controls (p < 0.05). |
Liu et al., 2019 [49] | 30 childhood T-ALL patients and 30 controls; China | qRT-PCR; whole blood | Significantly higher expression of miR-663b in children with T-ALL compared with controls (p < 0.01). |
Piatopoulou et al., 2018 [50] | 125 childhood ALL cases at diagnosis and 64 controls; Greece | qRT-PCR; BM | Levels of miR-143 and miR-182 were significantly lower in ALL patients compared to controls (p < 0.001). Univariate logistic regression for miR-143 (OR, 0.108; 95% CI: 0.056 to 0.207; p < 0.001) and miR-182 (OR, 0.221; 95% CI: 0.126 to 0.386; p < 0.001) and ROC curve analysis revealed a strong clinical significance of both miR-143 and miR-182 in differential diagnosis of childhood ALL (AUC, 0.88; 95% CI: 0.831 to 0.928; p < 0.001 and AUC, 0.762; 95% CI: 0.694 to 0.829; p < 0.001; respectively). Multivariate logistic regression analysis highlighted that lower levels of miR-143 (OR, 0.115; 95% CI: 0.054 to 0.245; p < 0.001) can discriminate leukemic from normal BM specimens, independently of patient age and gender. |
Swellam et al., 2018 [51] | 43 childhood ALL patients at diagnosis and 23 controls; Egypt | qRT-PCR; whole blood | Expression levels of miR-125b-1 were 32.6-fold higher in ALL cases as compared to controls (median: 66.67 vs. 2.04; p < 0.0001), whereas expression of miR-203 was 30.76-fold higher in controls than in ALL patients (median: 20.34 vs. 0.66; p < 0.0001). ROC analysis for miR-203 displayed better sensitivity scores than miR-125b-1: (a) miR-203: AUC, 0.874; 95% CI: 0.769 to 0.942; p < 0.0001; cutoff 0.973; 97.7% sensitivity; 87% specificity, (b) miR-125b-1: AUC, 0.858; 95% CI: = 0.715 to 0.847; p < 0.0001; cutoff 3.209; 83.7% sensitivity; 100% specificity; (c) miR-125b-1 combined with miR-203: 100% sensitivity; 87% specificity; 93.5% positive predictive value; 100% negative predictive value; 95.5% accuracy. These two miRNA expression levels were negatively correlated (r = −0.302; p = 0.014). |
Ghodousi et al., 2018 [52] | 46 childhood ALL patients at diagnosis and 16 controls; Iran | qRT-PCR; BM | Both miR-326 and miR-200c expression levels were significantly lower in ALL patients than controls (p = 0.0002 and 0.035, respectively). ROC curve analysis revealed a high AUC for miR-326 (0.813; 95% CI: 0.671 to 0.954; cutoff, 0.29; sensitivity, 83.3%; and specificity, 70.8%; p < 0.001), whereas the AUC for miR-200c was 0.79 (95% CI: 0.649 to 0.932; cutoff, 0.42; sensitivity, 66.7%; and specificity, 71.4%; p = 0.004). |
Shafik et al., 2018 [53] | 70 childhood ALL patients at diagnosis and 7 controls; Egypt | qRT-PCR; BM | Expression of miR-128 was significantly elevated in ALL patients compared with controls (p < 0.001). |
Jiang et al., 2018 [54] | 92 children with ALL (both at diagnosis and relapsed) and 3 controls; China | qRT-PCR; BM and plasma | Expression of miR-652-3p was significantly lower in ALL patients at diagnosis compared with healthy controls (p < 0.05). In the same study, a total of 45 miRNAs were documented as significantly downregulated in newly diagnosed patients compared with controls (i.e., 3661.7-fold downregulation of miR-22 in ALL patients compared to controls; p = 00002): miR-22, miR-624, miR-29a*, miR-183, miR-190b, miR-339-5p, miR-501-3p, miR-200b, miR-195, mmu-miR-140, miR-487b, miR-301, miR-200c, miR-106b, miR-502-3p, miR-18a, miR-27a, SNORD48 X2, miR-142-5p, miR-142-3p, miR-15a*, miR-196b, miR-340*, miR-183*, miR-191*, miR-205, miR-370, miR-29a, miR-532-3p, miR-532, miR-324-3p, miR-20b, miR-138, miR-26b, miR-433, miR-550, miR-19b, miR-136*, miR-1290, miR-374, miR-1180, miR-642, miR-10b, mmu-miR-93, miR-15b, miR-20a*, miR-500, miR-223, miR-652, miR-20a, miR-27b, miR-19a, dme-miR-7, miR-22*, miR-30c, miR-30b and miR-769-5p. |
Zang et al., 2018 [55] | 81 childhood ALL patients and 83 controls; China | qRT-PCR; whole blood | Significant downregulation of miR-9 in T-cells obtained from ALL patients relative to controls (p < 0.05). Induced overexpression of miR-9 inhibited ALL development in vitro via its downstream target, neuropilin-1 (NRP1). |
Asnafi et al., 2017 [56] | 41 children with ALL and 41 controls; Iran | qRT-PCR; BM and whole blood | Expression of miR-21 and miR-150 was downregulated in ALL patients compared with controls (unknown significance), whereas miR-451 expression displayed no difference. |
Piatopoulou et al., 2017 [57] | 125 childhood ALL patients at diagnosis and 64 controls; Greece | qRT-PCR; BM | Expression analysis revealed the significant downregulation of miR-125b levels in childhood ALL patients compared to controls (p < 0.004). The discriminatory significance of miR-125b for childhood ALL from healthy children was confirmed by univariate logistic regression (OR, 0.477; 95% CI: 0.288 to 0.790; p = 0.004) and ROC analysis (AUC, 0.628; 95% CI: 0.548 to 0.707; p = 0.004). The discriminatory value of miR-125b seems to be independent of patient age and gender according to the adjusted multivariate logistic regression model (OR, 0.507; 95% CI: 0.305 to 0.842; p = 0.009). |
Nabhan et al., 2017 [58] | 30 childhood ALL patients at diagnosis and 30 controls; Egypt | qRT-PCR; serum | Significant downregulation of miR-181a in children with ALL compared with controls (p < 0.01). The previous finding were associated with SMAD7 overexpression and TGF-β1 downregulation (increasing proliferation and decreasing apoptosis). ROC curve analysis revealed an AUC of 0.93 (cutoff, 0.97; 86.5% sensitivity; 93.3% specificity; miR-181a positivity rate, 86.7%; p < 0.01). Serum levels of SMAD7, TGF-β1 (cutoff values ≥400.1 pg/mL and ≤0.25 ng/mL, respectively) and miR-181a seem to discriminate ALL cases from controls with 100% sensitivity, 93.3% specificity, 96.7% accuracy, 100% negative predictive value and 93.7% positive predictive value. |
Yuan et al., 2017 [59] | 111 childhood ALL patients and 111 controls with fractures; China | qRT-PCR; plasma | The expression levels of let-7f-5p, miR-5100 and miR-25-3p in ALL patients were significantly lower than in controls (p < 0.01). After adjusting for confounders, risk for ALL (OR and 95% CI) was calculated to be 0.84 (0.76 to 0.92), 0.81 (0.73 to 0.9) and 0.81 (0.74 to 0.89), respectively (p < 0.01 in all instances). ROC analysis and reclassification analysis showed that utilization of all three miRNAs, compared to established risk factors, can improve the AUC and improve diagnosis (0.78; 95% CI: 0.72 to 0.84; p = 0.012). |
Labib et al., 2017 [60] | 75 childhood B-ALL patients at diagnosis and 50 controls; Egypt | qRT-PCR; BM and serum | Significant upregulation of miR-21 in children with B-ALL compared to controls (9.62 ± 3.23 vs. 2.56 ± 0.83; p < 0.001; cutoff, 9.83 for high and low expression). ROC curve analysis revealed an AUC of 0.879 (88.7% sensitivity; 71.8% specificity; cutoff, 3.23) in distinguishing ALL patients from controls. |
Tian et al., 2017 [61] | 189 childhood B-ALL cases and 189 controls; China | qRT-PCR; N/A | Significant downregulation of miR-3173 in children with B-ALL compared to controls (p < 0.001). |
Ramani et al., 2017 [62] | 60 childhood B-ALL patients and 17 controls; the Netherlands | qRT-PCR; BM or PBMCs | The analysis revealed a signature of 136 significantly (p < 0.05; 45 of them with p < 10−5) differentially expressed miRNAs distinguishing pediatric patients with ALL from controls. Significant upregulation in ALL: miR-133b, miR-302, miR-190, miR-520, miR-10b, miR-515-5p, miR-517b, miR-501, miR-129, miR-155, miR-217, miR-330, miR-513, miR-585, miR-645, miR-617, miR-15b, miR-23a, miR-362, miR-368, miR-425-5p, miR-576 and miR-369-5p. Significant downregulation in ALL: miR-193b, miR-325, miR-514, miR-22, miR-7g, miR-7d, miR-302d, miR-206, miR-494, miR-101, miR-126, miR-100, miR-29a, miR-299-3p, miR-146, miR-20a, miR-374, miR-216, miR-532, miR-25, miR-30c and miR-30e-3p. |
Cao et al., 2016 [63] | 42 childhood ALL patients and 20 controls; China | qRT-PCR; BM | Significant downregulation of miR-34b in ALL patients compared with controls (1.65 ± 0.69 vs. 5.22 ± 1.15; p = 0.012). |
Lou et al., 2016 [64] | 20 childhood B-ALL patients and 20 controls; China | qRT-PCR; BM | Expression of miR-187-5p was significantly upregulated in B-ALL samples compared with controls (p < 0.001). This miRNA seems to modulate the Wnt/b-catenin signaling pathway via direct targeting of DDK2, thus promoting ALL cell proliferation and inhibiting apoptosis. |
Swellam et al., 2016 [65] | 85 childhood ALL patients at diagnosis and 25 controls; Egypt | qRT-PCR; PBMCs | Significant upregulation of miR-100 (median: 61.777 vs. 2.04; range: 0.14–259.39 vs. 0.173–3.029; p = 0.007) and miR-146a (121.3 vs. 2.05; 14.3–222.55 vs. 0–144; p < 0.0001) in ALL patients compared with controls. Significant downregulation of miR-196a (0.369 vs. 0.511; 0.001–144 vs. 0.08–0.973; p = 0.028) in ALL samples compared with controls. ROC analysis revealed a significant AUC for miRNA-146a (1; 95% CI: 0.956 to 1; SE 0; 100% sensitivity; 100% specificity; cutoff, 3.727; p < 0.0001) and miR-100 (0.87; 95% CI: 0.779 to 0.934; SE 0.038; 82.76% sensitivity; 100% specificity; cutoff, 3.029; p = 0.0001) in discriminating ALL patients from controls. |
de Oliveira et al., 2015 [66] | 128 childhood ALL patients at diagnosis and 11 controls; Brazil | qRT-PCR; BM | Significantly higher miR-708-5p expression in ALL samples compared with controls (p < 0.05). High expression was documented specifically for pre-B ALL (p < 0.01). |
Wu et al., 2015 [67] | 40 infants with KMT2A-rearranged ALL (26 KMT2A-AFF1, 4 KMT2A-MLLT3, 5 KMT2A-MLLT1 and 5 KMT2A-germline) at diagnosis and 8 controls; Japan | qRT-PCR; BM or whole blood | In infant ALL cells with KMT2A fusion, let-7b was significantly downregulated compared with controls according to DNA hypermethylation of its gene-promoter region. |
Nemes et al., 2015 [68] | 24 childhood ALL patients and no controls; Hungary | qRT-PCR; bone marrow and whole blood | Significant downregulation of miR-21, miR-24 and miR-29b in T-ALL patients compared to controls (p < 0.05). Significant upregulation of miR-155 in B-ALL patients compared to controls (p < 0.05). Significant upregulation of miR-128b in both B- and T-ALL children compared with controls (p < 0.05). Expression profiles of miRNAs were not significantly different between peripheral blood and bone marrow samples derived from the same patient. |
Luna-Aguirre et al., 2015 [69] | 19 childhood B-ALL patients at diagnosis and 7 adult controls; Mexico | qRT-PCR; plasma | A total of 40 significantly overexpressed miRNAs in B-ALL patients compared to controls: miR-511, miR-34a*, miR-565, miR-34a, miR-10b*, miR-630, miR-610, miR-181a, miR-181c, miR-222, miR-138-1*, miR-363, miR-144*, miR-451, miR-99a, miR-155, miR-886-3p, miR-223*, miR-422a, miR-146a, miR-192, miR-190b, miR-95, miR-140-3p, miR-660, miR-886-5p, miR-25, miR-320, miR-30e, miR-16, miR-19b, miR-500, miR-29a, miR-502-3p, miR-195, miR-20b, miR-579, miR-7, miR-19a and miR-768-3p. A total of 37 miRNAs significantly downregulated in B-ALL patients compared with controls: miR-199a-3p, miR-340*, miR-151-3p, miR-335, miR-99b, miR-425*, miR-224, miR-221, miR-744, miR-15b, miR-223, miR-26a, miR-454*, miR-452, miR-491-5p, miR-340, miR-196b, miR-301a, miR-324-5p, miR-126*, miR-152, miR-330-3p, miR-652, miR-374b, miR-148b, miR-671-3p, miR-18a, let-7d, miR-339-3p, miR-126, miR-30b, miR-148b*, miR-27a, miR-30c, miR-374a, miR-331-3p and miR-28-5p. Diagnostic capacity for miR-511 (overexpressed in B-ALL; range, 3.32 to 12.98; cutoff, 9.458; AUC, 1; 100% sensitivity, specificity, PPV and NPV), miR-34a (overexpressed; range, 0.73 to 7.55; cutoff, 7.179; AUC, 0.98; 92% sensitivity; 100% specificity and PPV; 70% NPV), miR-222 (overexpressed; range, −1.5 to 3.12; cutoff, −0.1325; AUC, 0.91; 79% sensitivity; 100% specificity and PPV; 54% NPV), miR-26a (underexpressed; range, −1.63 to −9.17; cutoff, 2.073; AUC, 0.91; 79% sensitivity; 100% specificity and PPV; 47% NPV), miR-221 (underexpressed; range, 1.1 to −8.21; cutoff, −0.1861; AUC, 0.92; 83% sensitivity; 100% specificity and PPV; 54% NPV) and miR-223 (underexpressed; range, 0.31 to −8.52; cutoff, −4.309; AUC, 0.93; 89% sensitivity; 100% specificity and PPV; 64% NPV) showed that miR-511 could be used as a circulating biomarker for B-ALL detection. Moreover, miR-199a-3p (most underexpressed compared to controls; RQ, -13.48; p < 0.001), along with miR-511 (most overexpressed; RQ, 159.55; p = 0.002), might be associated with the pathogenesis of B-ALL. |
Organista-Nava et al., 2015 [70] | 111 childhood ALL patients and 100 controls; Mexico | qRT-PCR; BM and/or whole blood | Significantly lower miR-24 expression in ALL patients compared with controls (median, 0.84; p = 0.002). |
Oliveira et al., 2015 [71] | 37 childhood T-ALL patients and normal T-cells; Brazil | qRT-PCR; BM or whole blood | Significantly lower miR-29a expression in T-ALL patients compared with control T-cells. |
Duyu et al., 2014 [28] | 43 childhood ALL patients at diagnosis and 14 controls; Turkey | qRT-PCR and microarray; BM and whole blood | A total of 13 miRNAs (miR-548i, miR-708, miR-181b, miR-449a, miR-146a, miR-155, miR-181a*, miR-3121, miR-181a, miR-128, miR-1323, miR-195 and miR-587) showed upregulation, and 2 miRNAs (miR-640 and miR-145) showed downregulation in the microarray study. Confirmation analysis by qRT-PCR demonstrated only five upregulated miRNAs: miR-128, miR-146a, miR-155, miR-181a and miR-195 (p < 0.05). Microarrays revealed significant upregulation of miR-548i, miR-3140, miR-181b, miR-3115, miR-548d-5p, miR-449a, miR-181c, miR-181a, miR-181a*, let-7b*, miR-1827, miR-92a-1*, miR-299-3p, miR-155, miR-181a-2*, miR-1323, miR-587, miR-7-1*, miR-28-3p, miR-130b, miR-27b and miR-361-5p and significant downregulation of miR-633, miR-326, miR-501-3p, miR-802, miR-4260, miR-3130-5p, miR-145, miR-186, miR-593*, miR-574-3p, miR-4262, miR-640 and miR-606 in T-ALL patients compared to controls. Significant upregulation of miR-708, miR-181b, miR-369-3p, miR-146a, miR-155, miR-195 and miR-128 and significant downregulation of miR-143 and miR-145 in children with B-ALL compared with healthy controls. Intriguingly, miRNAs from peripheral blood samples were not correlated with BM samples. |
Malik et al., 2014 [72] | 30 childhood B-ALL and 20 T-ALL patients and 50 controls; India | qRT-PCR; PBMCs | Significantly higher expression of miR-2909 in both B- and T-ALL samples compared with controls (p < 0.01). |
Gimenes-Teixeira et al., 2013 [73] | 48 childhood T-ALL patients and 10 controls; Brazil | qRT-PCR; BM, PBMCs and thymic samples | Significantly higher miR-221 and miR-374 expression in T-ALL samples compared with controls (p < 0.05). |
Xue Li et al., 2013 [74] | 34 childhood common-ALL patients and 5 controls; China | Microarray; BM | Significantly upregulated expression of miR-708 (16.886 ± 16.854 vs. 1.872 ± 0.339; p < 0.01), miR-181b (5.710 ± 4.652 vs. 1.276 ± 0.531; p = 0.006) and miR-210 (9.789 ± 1.178 vs. 1.005 ± 0.08; p < 0.01) in children with common ALL compared with controls. Significant downregulation of miR-345 (0.675 ± 0.086 vs. 1.204 ± 0.143; p = 0.007) and miR-27a (0.523 ± 0.085 vs. 1.123 ± 0.066; p = 0.004) in common ALL compared with controls. |
Li et al., 2013 [75] | 111 childhood ALL patients and 10 controls; China | qRT-PCR; BM | The expression levels of miR-100 and miR-99a were significantly downregulated in ALL patients compared with controls (p = 0.001 and p = 0.0086, respectively). |
de Oliveira et al., 2012 [76] | 128 childhood ALL patients at diagnosis and 11 controls; Brazil | qRT-PCR; BM | Significantly lower expression of miR-100 (median, 0.21; range, 0.002 to 10.76; vs. 1.04 (0.34 to 3.9); p < 0.01)), miR-196b (0.03 (0.001 to 65.68) vs. 1.07 (0.29 to 3.7); p < 0.01) and let-7e (0.59 (0.04 to 5.15) vs. 1.16 (0.54 to 3.25); p < 0.01) and significantly higher expression of miR-128a (4.32 (0.16 to 167.91) vs. 1.02 (0.57 to 2.23); p < 0.01) and miR-181b (5.06 (0.07 to 45.09) vs. 1.41 (0.33 to 3.4); p < 0.01) in ALL samples compared to controls. The expression of miR-92a and miR-125a-5p was similar for both groups. |
Borze et al., 2011 [77] | 9 childhood ALL patients and 8 controls of N/A age; Finland | Microarray; BM | Significant upregulation of miR-142-3p (p = 0.001), miR-146a (p = 0.004), miR-222 (p = 0.012), miR-142-5p (p = 0.022), miR-150* (p = 0.032), miR-144 (p = 0.041) and miR-155 (p = 0.043) in ALL samples compared with controls. Significant downregulation of miR-768-5p (p < 0.001), miR-125b (p = 0.006), miR-223 (p = 0.007), miR-22 (p = 0.012), miR-27a (p = 0.027) and miR-15b (p = 0.032) in ALL patients compared with healthy donors. Similar expression levels of miRNAs between BM core biopsies (under decalcification and fixation with formalin) and BM aspirates. |
Bhatia et al., 2011 [78] | 10 childhood T-ALL patients at diagnosis and control T-cells; India | Semi-qRT-PCR; PBMCs | Significantly lower expression levels of miR-196b and miR-148a and significantly higher expression levels of miR-30b and miR-151 in children with T-ALL compared with normal T-cells (p < 0.05). Consequently, miR-196b was unable to downregulate MYC protooncogene expression in T-ALL patients as a result of mutations in the 3′-untranslated region (3′-UTR) of the target. |
Mavrakis et al., 2011 [79] | 50 childhood T-ALL patients at diagnosis and normal T-cell populations from pediatric thymuses; Belgium and France | qRT-PCR; BM and thymic T-cells | Significantly higher miR-223, miR-19b, miR-20a, miR-92, miR-142-3p, miR-150, miR-93, miR-26a, miR-16 and miR-342 expression in T-ALL samples compared with controls (p < 0.05). |
Stumpel et al., 2011 [80] | 5 t(4;11)-positive ALL infants at diagnosis and 7 controls; the Netherlands | qRT-PCR; BM | Significant downregulation of miR-10a, miR-101, miR-148a, miR-152, miR-200a, miR-200b, miR-424, miR-429, miR-432, miR-486 and miR-503 in KMT2A-rearranged ALL samples compared with controls (via hypermethylation). |
Schotte et al., 2011 [81] | 70 childhood ALL patients at diagnosis and 10 controls; the Netherlands | RNA-seq and qRT-PCR; BM and PBMCs | Significant downregulation of miR-3136 and miR-4474 in ALL patients compared to controls. |
Bhatia et al., 2010 [82] | 10 ALL patients of N/A age and normal B-cells; India | RT-PCR; PBMCs | Significant downregulation of miR-151, miR-196b and miR-148a in patient samples compared with B-cells obtained from healthy volunteers (p < 0.05). Among them, only miR-196b was found to be downregulated in the EB-3 cell line (potential tumor-suppressive function), whereas it seemed to downregulate the highly expressed MYC and, in turn, to decrease the expression of MYC effector genes (TERT, BCL2 and AATF). |
Schotte et al., 2009 [83] | 92 childhood ALL patients at diagnosis (20 MLL-rearranged, 57 B-ALL and 15 T-ALL) and normal CD34+ progenitor cells from 2 children with brain tumors; the Netherlands | qRT-PCR; BM or whole blood | Significant upregulation of miR-128a, miR-142-3p and -5p, as well as miR-150, miR-151-5p (not in KMT2A-rearranged cases), miR-181a, miR-181b, miR-181c, miR-193a, miR-30e-5p, miR-34b, miR-365, miR-582 and miR-708 (p ≤ 0.001) in ALL patients compared with controls. Significant downregulation of miR-100, miR-125b, miR-99a and let-7e in children with ALL compared with controls (p < 0.001). Conversely, miR-196b was found to be significantly downregulated in B-other cases (p < 0.001) and significantly upregulated in KMT2A-rearranged cases (p = 0.021) compared to controls. |
Zhang, Yang, et al., 2009 [84] | 24 childhood ALL patients at diagnosis and 3 controls; China | qRT-PCR; BM | Significantly higher expression levels of miR-9, miR-9*, miR-181a, miR-128, miR-181b, miR-130b and miR-363 in children with ALL compared with controls. Significantly lower expression of miR-7e, miR-30a, miR-199b-3p, miR-126, miR-143, miR-223 and miR-582-5p in ALL samples compared to controls. With respect to novel miRNAs miR-1943, miR-1841, miR-1931, miR-1987, miR-1890 and miR-1902 were upregulated, and miR-1859, miR-1859*, miR-1947, miR-1971, miR-1866, miR-1986, miR-1843, miR-1852, miR-1852*, miR-1842, miR-1834, miR-1971* and miR-1893 were down regulated in ALL specimens compared with controls (p < 0.001). |
Ju et al., 2009 [85] | 40 childhood pre-B-ALL patients at diagnosis and 6 controls; China | Microarray and qRT-PCR; BM | Significantly higher expression levels of miR-339 (p < 0.001), miR-222 (p = 0.0061) and miR-142-3p (p < 0.001) and significantly lower expression of miR-451 and miR-373* (p < 0.001) in ALL samples compared with controls. Upregulation of miR-361, miR-487b and miR-519e and downregulation of miR-296, miR-485-3p and miR-483 in ALL specimens compared with controls in microarrays, although not been confirmed by qRT-PCR. |
Zhang, Luo, et al., 2009 [86] | 18 childhood ALL patients and 7 controls (validation cohort: 31 ALL cases and 5 controls); China | Microarray and qRT-PCR; BM | Significantly higher expression of miR-146a, miR-34a, miR-210, miR-213, miR-181c, miR-126, miR-181a, miR-181d, miR-130a, miR-195, miR-181b, miR-130b, miR-155, miR-17-3p, miR-128b, miR-128a, miR-18b, miR-28, miR-331, miR-505 and miR-363 and significantly lower expression of miR-582, miR-142-5p, miR-145, miR-143, miR-338, miR-148a, miR-424, miR-24, miR-29a, miR-199b and miR-199a in children with ALL compared with controls. |
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Kyriakidis, I.; Kyriakidis, K.; Tsezou, A. MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia: Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools. Cancers 2022, 14, 3976. https://doi.org/10.3390/cancers14163976
Kyriakidis I, Kyriakidis K, Tsezou A. MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia: Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools. Cancers. 2022; 14(16):3976. https://doi.org/10.3390/cancers14163976
Chicago/Turabian StyleKyriakidis, Ioannis, Konstantinos Kyriakidis, and Aspasia Tsezou. 2022. "MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia: Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools" Cancers 14, no. 16: 3976. https://doi.org/10.3390/cancers14163976
APA StyleKyriakidis, I., Kyriakidis, K., & Tsezou, A. (2022). MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia: Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools. Cancers, 14(16), 3976. https://doi.org/10.3390/cancers14163976