NTRK Fusion Genes in Thyroid Carcinomas: Clinicopathological Characteristics and Their Impacts on Prognosis

Abstract

Chromosomal rearrangements of <i>NTRK</i> genes are oncogenic driver mutations in thyroid cancer (TC). This study aimed to identify <i>NTRK</i> 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 <i>BRAF</i>, <i>HRAS</i>, <i>KRAS</i>, <i>NRAS, RET</i>, <i>RET/PTC</i> or <i>PAX8/PPARγ</i> mutation were excluded from further analyses. <i>NTRK</i> fusion gene testing was performed in 259 cases, including 126 cases using next-generation sequencing. <i>NTRK</i> 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 <i>NTRK</i> fusions were found, including <i>ETV6/NTRK3</i>, <i>EML4/NTRK3</i>, <i>RBPMS/NTRK3</i>, <i>SQSTM1/NTRK3</i>, <i>TPM3/NTRK1</i>, <i>IRF2BP2/NTRK1</i>, <i>SQSTM1/NTRK1</i> and <i>TPR/NTRK1.</i><i>NTRK</i> fusion-positive carcinomas were associated with the follicular growth pattern, chronic lymphocytic thyroiditis and lymph node metastases. <i>NTRK1</i>-rearranged carcinomas showed a higher frequency of multifocality and aggressivity than <i>NTRK3</i>-rearranged carcinomas. Tumor size, presence of metastases, positivity for the <i>NTRK3</i> or <i>NTRK1</i> fusion gene and a late mutation event (<i>TERT</i> or <i>TP53</i> mutation) were determined as factors affecting patient prognosis. <i>NTRK</i> fusion genes are valuable diagnostic and prognostic markers.