Prognostic Significance of Key Molecular Markers in Thyroid Cancer: A Systematic Literature Review and Meta-Analysis

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.