Characterizing Genetic Alterations Related to Radioiodine Avidity in Metastatic Thyroid Cancer

Abstract

Context: Patients with differentiated thyroid cancer (DTC) with distant metastasis (DM) are usually not recognized as radioactive iodine (RAI)refractory DTC in a timely manner. The elucidation of genetic features related to RAI uptake patterns may shed light on the early recognition of RAI-refractory DTC. Objective: This work aimed to elucidate the underlying molecular features behind different RAI uptake patterns. Methods: A total of 214 patients with DM-DTC were retrospectively included in the analysis. RAI uptake patterns were defined as initially RAI refractory (I-RAIR) and initially RAI avid (I-RAIA) according to the first post-treatment scan, then I-RAIA was further divided into continually RAIA (C-RAIA), partly RAIR (P-RAIR), and gradually RAIR (G-RAIR) according to subsequent scans. The molecular subtype groups—BRAFV600E mutated, RAS mutated, fusions, and others—were classified according to main driver genes status. Results: BRAF, TERT promoter, and TP53 mutations are more frequently detected in the I-RAIR pattern while RET fusions and RAS mutations are more frequent in the I-RAIA pattern. A late-hit mutation including TERT, TP53, or PIK3CA is more common in I-RAIR than that in I-RAIA (50.0% vs 26.9%, P = .001), particularly for those with RAS mutations in the I-RAIR group, always accompanied by TERT promoter. Isolated RET fusions accounts for 10% of I-RAIR. When compared among driver gene groups, BRAFV600E-mutated tumors have a higher rate of the I-RAIR pattern (64.4%) than RAS-mutated (4.5%, P < .001) and fusion-positive (20.7%, P