Molecular Genetic Profile of Patients with Differentiated Thyroid Carcinoma Belonging to the Intermediate and High Postoperative Risk Groups for Recurrence

BACKGROUND: Among differentiated thyroid carcinoma (DTC) cases, patients classified into the intermediate and high postoperative risk groups for recurrence account for over at least 35% of all cases. However, the optimal management strategy, the clinical utility of radioiodine therapy (RAIT), and the factors determining its efficacy remain insufficiently elucidated. Although the prognostic significance of mutations in BRAF, TERT, TP53, and RAS genes has been well described, their impact on the functional activity of the sodium–iodide symporter (NIS), the degree of cellular differentiation, and the relationship with RAIT responsiveness has not been clearly established.

AIM: To assess the relationship between the mutational profile of the primary tumor and clinical outcomes after RAIT in patients with intermediate/high-risk DTC, and to identify candidate genes associated with poor therapeutic response.

MATERIALS AND METHODS: Next-generation sequencing (NGS) was performed on DNA extracted from formalin-fixed paraffin-embedded (FFPE) samples of primary DTC tumors (N=28). Clinical and anamnestic data of patients meeting inclusion criteria were retrospectively analyzed. The MEDLINE, Google Scholar, and STRING databases were searched for candidate genes implicated in NIS regulation and poor RAIT response. Of the 68 potential genes, 51 distinct mutations were identified in the analyzed samples. Statistical analysis was conducted to evaluate the correlation between clinical characteristics and molecular profiles using Statistica v.12 software (TIBCO Software Inc., USA).

RESULTS: The median follow-up duration was 22.5 [16; 62] months. The median number of somatic variants per patient detected by the targeted sequencing panel was 4.5 [3; 8] (range 1–22). The most frequent variants involved BRAF, PTEN, PIGU, and TG. In the subgroup with unfavorable outcomes, clustering of mutations was observed in BRAF, COL5A1, CTNNB1, DUOX2, AKT1, ALK, ERBB2, GLI1, HORMAD2, IYD, NOTCH3, SLC5A8, SMAD3, and TSHR. The difference in the total number of somatic variants between outcome groups did not reach statistical significance (p=0.755). The presence of distant metastases (M1) emerged as a strong predictor of poor outcome (p<0.001), while coexisting autoimmune thyroiditis had no significant impact (p=0.309).

CONCLUSION: The absence of a significant difference in the number of somatic variants between patients with favorable and unfavorable responses (p=0.755), together with the clustering of pathogenic mutations in specific genes in the radioiodine-refractory group, suggests that the activation of specific oncogenic signaling pathways, rather than overall genomic instability, is a key determinant of tumor behavior in this solid tumor type. Resistance or incomplete response to radioiodine therapy may result from the concurrent activation of multiple oncogenic signaling pathways, including MAPK, PI3K/AKT/ mTOR, TSH–TSH receptor, TGF-β/SMAD3, Sonic Hedgehog, and β-catenin/Wnt signaling. Further evaluation of candidate genes implicated in aggressive disease behavior in differentiated thyroid cancer is warranted in larger patient cohorts, with particular emphasis on transcript-level expression analyses.

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