Introduction
Nowadays, the search for minimally invasive biomarkers for early cancer detection remains a priority. Although colorectal cancer (CRC) screening programs are well established worldwide, they face important limitations, including the limited sensitivity of non-invasive tests, such as the Fecal Immunochemical Test (FIT), which performs suboptimally in detecting precancerous lesions and also contributing to the high number of unnecessary colonoscopies. This underscores the need for more accurate biomarkers, namely blood-based microRNAs, to improve screening strategies and patient adherence.
Aims & Methods
This study aims to validate circulating miRs models for the early detection of CRC. Based on our previous literature review, we selected four miRs: miR-21-5p, miR-92a-3p, miR-451a and miR-199a-5p, with the best performance for the detection of CRC and high-grade dysplasia lesions (HGD) for validation. MiR expression was evaluated using RT-qPCR in plasma samples from 252 individuals who underwent colonoscopy, after a positive FIT result, with different clinical phenotypes: individuals without lesions (n = 63), with low-grade dysplasia (LGD - n = 62), with high-grade dysplasia (n = 63), and with CRC (n = 64). Logistic regression models were built using miRs expression data and clinical variables such as age and gender.
Results
Our findings demonstrate a downregulation of all miRs in CRC and HGD lesions compared with individuals without lesions and those with LGD. After logistic regression analysis, three blood miR-based panels were developed. A panel compose of the differential expression of miR-21-5p, miR-92a-3p, miR-451a, along with age and gender (Panel A) showed a good screening performance for identifying colorectal lesions (LGD, HGD, and CRC), achieving an AUC of 0.76 (95% CI: 0.70–0.80), with a sensitivity of 62% (95% CI: 45–73%) and a specificity of 78% (95% CI: 63–89%). Moreover, the combination of miR-92a-3p, miR-451a, miR-199a-5p and age (Panel B) also demonstrated a good discriminatory power for HGD lesions, with an AUC of 0.76 (95% CI: 0.70–0.81), a sensitivity of 62% (95% CI: 38–77%), and a specificity of 82% (95% CI: 63–91%). Finally, for CRC discrimination, the combination of miR-21-5p and miR-92a-3p and gender (Panel C) showed good screening value, yielding an AUC of 0.78 (95% CI: 0.73–0.82), a sensitivity of 66% (95% CI: 49–80%), and a specificity of 75% (95% CI: 60–88%). Additionally, when combining the results of Panel B and C, the sensitivity for detecting HGD and CRC lesions increased to 87% (95% CI: 83–89%), with a specificity of 61% (95% CI: 52–68%). Furthermore, applying this approach after a positive FIT result, could correctly classify 61% of FIT false positivity results.
Conclusion
The findings obtained in this study suggest that, following a positive FIT result, circulating miRs-based models have the potential to enhance the accuracy in detecting colorectal precancerous (HGD) and cancerous (CRC) lesions and consequently decrease the false-negative results. Moreover, this approach could serve as an effective clarifying screening tool, as it may also reduce false positives results, and consequently, clinical burden, by minimizing the number of unnecessary colonoscopies.
