Background: Thyroid cancer (TC) involves diverse genetic alterations, with their prognostic significance often debated. Objectives: This study evaluates the impact of BRAF, TERT promoter, TP53, and PI3K pathway mutations detected via Next-Generation Sequencing (NGS) on overall survival (OS) and disease-free survival (DFS) in follicular-derived TC patients. Methods: A comprehensive search was conducted in MEDLINE, Scopus, and EMBASE databases from 2013 to 2023 for studies using NGS on TC patients. Hazard ratios (HR) and 95% confidence intervals (CI) for OS and DFS were extracted from original studies or estimated from Kaplan–Meier curves (KMC). A random-effects model, weighted by inverse variance, was used to calculate pooled HRs. Publication bias was assessed using Egger’s regression test and visual funnel plot analysis. Results: Of the 3921 initial studies, nine studies involving 1075 patients were included in the meta-analysis. BRAF mutations showed no significant effect on OS (HR = 1.11, 95% CI: 0.66–1.88) or DFS (HR = 1.23, 95% CI: 0.66–2.29). In contrast, TERT promoter mutations were strongly associated with worse OS (HR = 1.90, 95% CI: 1.17–3.09) and DFS (HR = 2.76, 95% CI: 1.86–4.10). TP53 and PI3K pathway mutations were linked to shorter OS (HR = 2.87, 95% CI: 1.44–5.86 and HR = 2.17, 95% CI: 1.05–4.15, respectively), though their impact on DFS remains unclear due to limited data. Conclusions: These findings highlight TERT promoter mutations as strong prognostic markers for both OS and DFS, while TP53 and PI3K mutations indicate higher mortality risk.

Somatic mutations in the telomerase reverse transcriptase (TERT) promoter are key molecular events in thyroid carcinogenesis and are strongly associated with aggressive clinical behaviour. The c.-124C>T and c.-146C>T hotspot mutations, discovered in 2013, are now recognised as major mechanisms of TERT reactivation and as independent predictors of disease-specific survival, recurrence, and disease refractoriness to radioiodine. TERT can also be reactivated by multiple regulatory layers converging on telomerase upregulation. Beyond telomere maintenance, TERT enhances ribosome biogenesis, cooperates with BRAFV600E-driven transcriptional programmes, and modulates NF-κB-associated inflammatory and stress responses, thereby promoting dedifferentiation and therapy resistance. Clinically, TERT promoter mutations, particularly when co-occurring with BRAFV600E, increase in prevalence from papillary to anaplastic thyroid carcinoma and are associated with an increased risk of radioiodine-refractory disease, supporting their use in risk stratification. However, isolated TERT promoter mutations are more often associated with intermediate risk tumours and comparatively better outcomes, underscoring the importance of molecular context. The recent approval of the telomerase inhibitor imetelstat and the preclinical success of the rRNA transcription inhibitor CX5461 in restoring differentiation and iodine uptake support telomerase- and ribosome-targeted strategies as emerging therapeutic avenues for TERT-driven thyroid cancers.