Circulating miRNAs for Early-Onset Colorectal Cancer: Pooled Accuracy and Study Limits

Blood-based circulating miRNAs were assessed as early-onset colorectal cancer (EOCRC) biomarkers in a systematic review and meta-analysis that the authors report shows promising pooled diagnostic accuracy alongside marked cross-study variability. Synthesizing published diagnostic evaluations, the review frames single-miRNA assays as a liquid-biopsy approach that could distinguish EOCRC cases from controls in existing datasets. The authors also note that methodological differences and study-level limitations complicate interpretation of pooled estimates. The opening closes by highlighting gaps in standardization and risk-of-bias signals that accompany the summary performance results.

The meta-analysis included 16 studies comprising 27 study-level miRNA diagnostic evaluations overall, with the primary EOCRC-restricted pooled estimates derived from a subset of these evaluations. Across included reports, all studies quantified miRNAs using qRT-PCR, with serum used in most studies (15) and plasma used in one. The review describes broad variation in pre-analytic handling (including collection and processing workflows) and in analytical choices such as normalization strategies and cut-off selection. These differences are presented as a recurring backdrop for why results do not align cleanly across studies, with comparability repeatedly positioned as central to interpreting the aggregated evidence base.

In the primary EOCRC-restricted analysis, the authors report pooled sensitivity of 84.4% (95% CI 76.7–89.9%) and pooled specificity of 85.7% (95% CI 76.6–91.7%) for single circulating miRNAs. In a separate exploratory synthesis across all included CRC evaluations (not limited to EOCRC), the review reports pooled sensitivity of 85.7% (95% CI 79.9–90.0%) and pooled specificity of 85.1% (95% CI 79.4–89.5%), with an overall AUC described as greater than 0.90. The authors present these pooled results as summaries drawn from a mix of study populations and assay implementations rather than a single standardized test. The section ends by reiterating that the pooled estimates sit atop heterogeneous underlying evaluations.

Between-study inconsistency is emphasized throughout the results, with the authors reporting substantial heterogeneity and I² values frequently exceeding 85% across multiple diagnostic metrics. In QUADAS-2 assessment, the review reports that high risk of bias clustered in patient selection (87.5% of studies) and in the index test domain (87.5%), while the reference standard domain was rated low risk. The discussion links these patterns to the design and measurement variability described in study characteristics, including differences in enrollment approaches and analytic thresholds. Taken together, the authors describe heterogeneity and bias as key reasons pooled summaries may not translate uniformly across settings.

At the biomarker level, miR-21 was the most frequently evaluated single miRNA (five studies) and is described by the authors as a leading candidate based on reproducible performance signals and mechanistic plausibility. The paper also summarizes functional context by connecting miRNA dysregulation to CRC-related pathways that include Wnt/β-catenin, PI3K/AKT, and epithelial–mesenchymal transition (EMT) regulation. In its conclusion, the article characterizes the overall findings as hypothesis-generating and states that prospective validation in true screening cohorts, using standardized pre-analytic and analytic methods and multicenter harmonization, is needed before clinical implementation. This forward-looking framing is presented as the authors’ interpretation of what the current evidence can and cannot establish.

Key Takeaways:

• The authors report EOCRC pooled sensitivity of 84.4% (95% CI 76.7–89.9%) and pooled specificity of 85.7% (95% CI 76.6–91.7%) for single circulating miRNAs.
• Substantial heterogeneity was reported (I² often >85%), and QUADAS-2 concerns were described as concentrating in patient selection and index test domains (each 87.5%), with the reference standard domain rated low risk.
• The authors conclude that prospective, screening-based validation and standardized methods would be needed prior to clinical implementation.