Contribution to Diagnostic Accuracy and Prognostic Significance of MicroRNAs in Thyroid Cancer

Abstract

The incidence of thyroid cancer, the most common endocrine malignancy, has increased significantly, underscoring the need for improved diagnostic and prognostic methods. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression and play vital roles in cancer development. In thyroid cancer, they have gained attention as potential diagnostic and prognostic biomarkers. Current diagnostic methods, such as fine-needle aspiration cytology (FNAC), have limitations, particularly for indeterminate nodules (Bethesda III/IV), whereas conventional follow-up markers such as thyroglobulin (Tg) can be unreliable in certain patients. In this context, miRNAs offer a promising complementary approach. Several miRNAs, including miR-146b, miR-221, and miR-222, are consistently overexpressed in thyroid cancer and are associated with tumor presence and aggressive disease features. Circulating and exosomal miRNAs have shown good diagnostic accuracy in distinguishing malignant from benign thyroid nodules. Importantly, using multiple miRNA panels instead of single markers improves diagnostic performance and can reduce unnecessary surgeries in patients with indeterminate cytology. In addition to their diagnostic utility, miRNAs provide critical prognostic information. For instance, increased expression of miR-146b, miR-221, and miR-222 is associated with higher risk of recurrence, lymph node metastasis, and advanced tumor stages. In contrast, reduced expression of miRNAs such as miR-139-5p has been linked to persistent or progressive disease and unfavorable molecular features, including telomerase reverse transcriptase (TERT) promoter mutations. Furthermore, longitudinal changes in circulating miRNA levels may allow for early detection of disease progression, even when traditional biomarkers are inconclusive. At the molecular level, miRNAs operate within complex regulatory networks, including interactions with long non-coding RNAs and key signaling pathways to influence tumor growth and invasion. Their expression is also associated with common oncogenic mutations, such as those in the BRAF gene and RAS gene, suggesting a role in tumor heterogeneity and behavior. Recent studies highlight the potential of integrating miRNA profiles with other molecular data through multi-omics approaches, to improve risk stratification and support personalized treatment strategies. However, several challenges remain, including variability between studies, lack of standardized protocols, and limited large-scale prospective validation. In conclusion, miRNAs represent a promising and evolving class of biomarkers in thyroid cancer with direct applications in diagnosis, prognosis, and disease monitoring.