Abstract
Simple Summary The three-tiered American Thyroid Association (ATA) risk stratification helps clinicians tailor decisions regarding follow-up modalities and the need for postoperative radioactive iodine (RAI) ablation and radiotherapy. However, a significant number of well-differentiated thyroid cancers (DTC) progress after treatment. Current follow-up modalities have also been proposed to detect disease relapse and recurrence but have failed to be sufficiently sensitive or specific to detect, monitor, or determine progression. Therefore, we assessed the predictive accuracy of the microRNA-based risk score in DTC with and without postoperative RAI. We confirm the prognostic role of triad biomarkers (miR-2f04, miR-221, and miR-222) with higher sensitivity and specificity for predicting disease progression than the ATA risk score. Compared to indolent tumors, a higher risk score was found in progressive samples and was associated with shorter survival. Consequently, our prognostic microRNA signature and nomogram provide a clinically practical and reliable ancillary measure to determine the prognosis of DTC patients. To identify molecular markers that can accurately predict aggressive tumor behavior at the time of surgery, a propensity-matching score analysis of archived specimens yielded two similar datasets of DTC patients (with and without RAI). Bioinformatically selected microRNAs were quantified by qRT-PCR. The risk score was generated using Cox regression and assessed using ROC, C-statistic, and Brier-score. A predictive Bayesian nomogram was established. External validation was performed, and causal network analysis was generated. Within the eight-year follow-up period, progression was reported in 51.5% of cases; of these, 48.6% had the T1a/b stage. Analysis showed upregulation of miR-221-3p and miR-222-3p and downregulation of miR-204-5p in 68 paired cancer tissues (p < 0.001). These three miRNAs were not differentially expressed in RAI and non-RAI groups. The ATA risk score showed poor discriminative ability (AUC = 0.518, p = 0.80). In contrast, the microRNA-based risk score showed high accuracy in predicting tumor progression in the whole cohorts (median = 1.87 vs. 0.39, AUC = 0.944) and RAI group (2.23 vs. 0.37, AUC = 0.979) at the cutoff >0.86 (92.6% accuracy, 88.6% sensitivity, 97% specificity) in the whole cohorts (C-statistics = 0.943/Brier = 0.083) and RAI subgroup (C-statistic = 0.978/Brier = 0.049). The high-score group had a three-fold increased progression risk (hazard ratio = 2.71, 95%CI = 1.86-3.96, p < 0.001) and shorter survival times (17.3 vs. 70.79 months, p < 0.001). Our prognostic microRNA signature and nomogram showed excellent predictive accuracy for progression-free survival in DTC.