Abstract
Simple SummaryNTRK fusion genes are important but not well studied molecular markers in thyroid cancer. Their identification could help improve diagnosis and prognosis, and determine appropriate treatment. The aims of this study were to identify NTRK fusion-positive thyroid tumors in a large cohort of different thyroid tumors, to characterize these tumors by molecular, clinical and pathological features and to evaluate the impact of NTRK-rearranged tumors on prognosis of the disease. A suitable approach for selective NTRK fusion gene testing in thyroid cancer samples was created and utilized. In a cohort of 59 NTRK-rearranged carcinomas, characteristic features were described and recommendations for surgery and prognostic factors were determined thanks to the long-term follow-up of patients.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.
Highlights
Thyroid cancer (TC) is the most common endocrine malignancy with a still increasing incidence
The analyses revealed neurotrophic-tropomyosin receptor kinase (NTRK) fusion gene in 59 patients with TC, in 57 of 846 (6.7%) patients with papillary thyroid carcinoma (PTC) in 2 of 10 (20.0%) patients with poorly differentiated thyroid carcinoma (PDTC)
No NTRK fusion gene was detected in 16 MTCs, 13 FTCs, 9 anaplastic thyroid carcinoma (ATC), 10 Hürthle cell carcinoma (HCC), 30 borderline thyroid tumors or 190 benign thyroid tissues subjected to NTRK fusion analyses. cDNA from five formalin-fixed paraffinembedded (FFPE) PTCs and four benign fresh frozen thyroid tissues were not of sufficient quality for analyses
Summary
Thyroid cancer (TC) is the most common endocrine malignancy with a still increasing incidence. The clinical outcome of the disease is associated with various mutations occurring in TC. The most common mutation in TC is the BRAF V600E mutation, which has appeared to be associated with a higher risk of cancer recurrence [3]. This association has recently been disputed [4]. Differentiated thyroid tumors harboring RAS mutations without any co-alterations have excellent prognosis [6]. Other genetic alterations occurring in TC are rearrangements of NTRK, RET, ALK, BRAF, MET, FGFR, PPARγ or ROS1 genes whose associations with the outcome of the disease are not yet well known
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