Circulating miRNAs as liquid biopsy biomarkers for diagnosis in patients with colorectal cancer: a systematic review and meta-analysis

Abstract

Objective: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, emphasizing the need for noninvasive and reliable diagnostic tools. Circulating microRNAs (miRNAs) have emerged as promising liquid biopsy biomarkers for CRC detection. This meta-analysis aimed to evaluate the diagnostic accuracy of blood- and saliva-derived miRNAs in CRC, assessing their sensitivity, specificity, and overall clinical potential.

Methods: A comprehensive literature search was conducted across PubMed, Web of Science, and Scopus to identify relevant studies published between 2004 and 2024. Eligible studies included those that evaluated miRNA expression in plasma, serum, or saliva of CRC patients. A random-effects model was applied to calculate pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC). Heterogeneity was assessed using Cochrane's Q test and I² statistics, and risk of bias was evaluated using the QUADAS-2 tool.

Results: A total of 37 studies with 2,775 patients were included in this meta-analysis. The pooled diagnostic performance demonstrated an AUC of 0.87 for combined blood- and saliva-derived miRNAs and 0.86 for blood-derived miRNAs alone, with both categories showing a sensitivity of 0.76 and specificity of 0.83. The diagnostic likelihood ratio (DLR) analysis yielded DLR positive values > 4 and DLR negative values < 0.3, indicating strong discriminatory ability. The DOR was 15.98 for combined blood- and saliva-derived miRNAs and 15.49 for blood-derived miRNAs alone, highlighting their comparable diagnostic potential. These findings suggest that circulating miRNAs serve as reliable biomarkers for CRC detection.

Conclusion: This meta-analysis supports the diagnostic utility of circulating miRNAs as noninvasive biomarkers for CRC detection, with saliva-derived miRNAs offering a potential complementary role. Blood-based miRNA analysis demonstrated high diagnostic accuracy, and the integration of saliva-derived miRNAs slightly improved AUC. Future research should focus on standardizing miRNA panels and validation in larger, independent cohorts to facilitate their clinical application in CRC screening and early detection.

Keywords: biomarker; circulating biomarker; colorectal cancer; liquid biopsy; saliva diagnostics.

FIGURE 1

PRISMA flow diagram illustrating the study selection process. The diagram illustrates the number of records identified, screened, excluded, and included in the systematic review, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

FIGURE 2

Quality assessment of the included studies using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. The figure displays the proportions of included studies rated as low, unclear, or high risk of bias across four domains: patient selection, index test, reference standard, and flow and timing. Applicability concerns are shown separately for the first three domains. Green indicates low risk/concern, yellow indicates unclear, and red indicates high.

FIGURE 3

Pooled sensitivity and specificity for circulating miRNA-based diagnostics of colorectal cancer. (A) Combined blood- and saliva-derived miRNAs (Sensitivity: 0.76, Specificity: 0.83). (B) Blood-derived miRNAs alone (Sensitivity: 0.76, Specificity: 0.83).

FIGURE 4

Hierarchical summary receiver operating characteristic (HSROC) curve analysis for circulating miRNA-based colorectal cancer diagnostics. (A) Combined blood- and saliva-derived miRNAs (AUC: 0.87, 95% CI: 0.83–0.89). (B) Blood-derived miRNAs alone (AUC: 0.86, 95% CI: 0.83–0.89).

FIGURE 5

Diagnostic likelihood ratios (DLRs) for circulating miRNA-based colorectal cancer diagnostics. (A) Combined blood- and saliva-derived miRNAs (DLR positive: 4.54, DLR negative: 0.28). (B) Blood-derived miRNAs alone (DLR positive: 4.52, DLR negative: 0.29).

FIGURE 6

Diagnostic score (DS) and diagnostic odds ratio (DOR) for circulating miRNA-based colorectal cancer diagnostics. (A) Combined blood- and saliva-derived miRNAs (DS: 2.77, DOR: 15.98). (B) Blood-derived miRNAs alone (DS: 2.74, DOR: 15.49).

FIGURE 7

Deeks’ funnel plot assessing publication bias in circulating miRNA-based colorectal cancer diagnostics. (A) Combined blood- and saliva-derived miRNAs (p = 0.07). (B) Blood-derived miRNAs alone (p = 0.09).

FIGURE 8

Sankey plot visualizing the distribution of circulating miRNAs and their diagnostic performance. Each node represents an individual miRNA (left), categorized specificity (middle), or categorized sensitivity (right). Sensitivity and specificity were calculated for each miRNA based on extracted TP, FP, FN, and TN values from the included studies. Diagnostic performance was classified into three categories: High (≥0.85), Moderate (0.70–0.84), and Low (<0.70). The width of the flows between nodes is proportional to the number of studies reporting each miRNA and its associated diagnostic category. Spec, Specificity; Sens, Sensitivity.