The following is a summary of “Characterizing Genetic Alterations Related to Radioiodine Avidity in Metastatic Thyroid Cancer,” published in the May 2024 issue of Endocrinology by Mu, et al.

Patients with differentiated thyroid cancer (DTC) often face challenges in timely recognition of radioactive iodine (RAI)- refractory disease, particularly in cases with distant metastasis (DM). Understanding the genetic features associated with RAI uptake patterns could aid in the early identification of RAI-refractory DTC. For a study, researchers sought to uncover the molecular characteristics underlying different RAI uptake patterns in patients with DTC and distant metastasis.

A retrospective analysis included 214 patients with DM-DTC. RAI uptake patterns were classified as initially RAI refractory (I-RAIR) or initially RAI avid (I-RAIA), with further subcategorization of I-RAIA into continually RAI avid (C-RAIA), partly RAI refractory (P-RAIR), and gradually RAI refractory (G-RAIR). Molecular subtypes—BRAF^V600E mutation, RAS mutation, fusions, and others—were determined based on primary driver genes status.

In the analysis, BRAF, TERT promoter, and TP53 mutations were more commonly identified in the initially radioactive iodine refractory (I-RAIR) pattern, whereas RET fusions and RAS mutations were more prevalent in the initially radioactive iodine avid (I-RAIA) pattern. The occurrence of late-hit mutations involving TERT, TP53, or PIK3CA was significantly higher in I-RAIR compared to I-RAIA (50.0% vs. 26.9%, P = .001), particularly among cases with RAS mutations in the I-RAIR group, which were consistently accompanied by TERT promoter mutations. Isolated RET fusions were responsible for 10% of cases in the I-RAIR pattern. When comparing different driver gene groups, BRAF^V600E-mutated tumors exhibited a higher incidence of the I-RAIR pattern (64.4%) than RAS-mutated (4.5%, P < .001) and fusion-positive (20.7%, P < .001) tumors. Within the I-RAIA subgroups, BRAF^V600E-mutated tumors showed a lower prevalence of the continually radioactive iodine avid (C-RAIA) pattern compared to tumors with RAS mutations or fusions.

Patients with the I-RAIR pattern predominantly featured BRAF and/or TERT promoter mutations, often accompanied by RAS mutations, while fusions typically occurred alone. The findings provided insights into the molecular landscape associated with RAI uptake patterns in DTC with distant metastasis.

Reference: academic.oup.com/jcem/article/109/5/1231/7460630