Abstract
Background/Objectives: Radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC) is associated with limited treatment options and a less favorable clinical course. Combining molecular alterations with clinicopathological characteristics may improve the early identification of patients at risk of radioiodine refractoriness. This study aimed to evaluate the association between molecular genetic alterations, particularly BRAF and TERT promoter mutations, and RAIR-DTC. Methods: This retrospective single-center study conducted in Kazakhstan included 167 patients with differentiated thyroid carcinoma treated between 2021 and 2023. Patients were classified into radioiodine-sensitive (n = 130) and radioiodine-refractory (n = 37) groups. Clinical, histopathological, and molecular genetic characteristics were analyzed. Results: Radioiodine refractoriness was observed in all 13 patients (100.0%) with concurrent BRAF and TERT promoter mutations, compared with 24 of 154 patients (15.6%) without this co-mutation (OR = 163.46, 95% CI 9.31–2870.79; p < 0.001). The BRAF + TERT co-mutation was also associated with less differentiated histological architecture and a higher T category. In contrast, the BRAF mutation alone showed a substantially weaker association with radioiodine refractoriness, highlighting the incremental value of the combined BRAF + TERT molecular status. Conclusions: The concurrent presence of BRAF and TERT promoter mutations, rather than the BRAF mutation alone, may improve the identification of patients at increased risk of radioiodine refractoriness. Integrating molecular profiling with clinicopathological characteristics may support individualized risk stratification and treatment planning.