Carcinomas of the thyroid gland are some of the most common malignancies of the endocrine system. The causes of tumor transformation are genetic changes in genes encoding cell signaling pathways that lead to an imbalance between cell proliferation and apoptosis. Some mutations have been associated with increased tumor aggressiveness, metastatic lymph node spread, tendency to dedifferentiate, and/or reduced efficiency of radioiodine therapy. The main known genetic causes of thyroid cancer include point mutations in the BRAF, RAS, TERT, RET, and TP53 genes and the fusion genes RET/PTC, PAX8/PPAR-γ, and NTRK. Molecular genetic testing of the fine needle aspiration cytology of the thyroid tissue in the preoperative period or of the removed thyroid tissue in the postoperative period is becoming more and more common in selected institutions. Positive detection of genetic changes, thus, becomes a diagnostic and prognostic factor and a factor that determines the extent of the surgical and nonsurgical treatment. The findings of genetic research on thyroid cancer are now beginning to be applied to clinical practice. In preoperative molecular diagnostics, the aggressiveness of cancers with the most frequently occurring mutations is correlated with the extent of the planned surgical treatment (radicality of surgery, neck dissection, etc.). However, clear algorithms are not established for the majority of genetic alterations. This review aims to provide a basic overview of the findings of the most commonly occurring gene mutations in thyroid cancer and to discuss the current recommendations on the extent of surgical and biological treatment concerning preoperatively detected genetic changes.
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Chromosomal rearrangements of NTRK genes are oncogenic driver mutations in thyroid cancer (TC). This study aimed to identify NTRK fusion-positive thyroid tumors and to correlate them with clinical and pathological data and determine their prognostic significance. The cohort consisted of 989 different TC samples. Based on the detected mutation, samples were triaged, and those that were positive for a BRAF, HRAS, KRAS, NRAS, RET, RET/PTC or PAX8/PPARγ mutation were excluded from further analyses. NTRK fusion gene testing was performed in 259 cases, including 126 cases using next-generation sequencing. NTRK fusion genes were detected in 57 of 846 (6.7%) papillary thyroid carcinomas and in 2 of 10 (20.0%) poorly differentiated thyroid carcinomas. A total of eight types of NTRK fusions were found, including ETV6/NTRK3, EML4/NTRK3, RBPMS/NTRK3, SQSTM1/NTRK3, TPM3/NTRK1, IRF2BP2/NTRK1, SQSTM1/NTRK1 and TPR/NTRK1.NTRK fusion-positive carcinomas were associated with the follicular growth pattern, chronic lymphocytic thyroiditis and lymph node metastases. NTRK1-rearranged carcinomas showed a higher frequency of multifocality and aggressivity than NTRK3-rearranged carcinomas. Tumor size, presence of metastases, positivity for the NTRK3 or NTRK1 fusion gene and a late mutation event (TERT or TP53 mutation) were determined as factors affecting patient prognosis. NTRK fusion genes are valuable diagnostic and prognostic markers.
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