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

Abstract

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.

NTRK‐rearranged papillary thyroid carcinoma demonstrates frequent subtle nuclear features and indeterminate cytologic diagnoses

“…Most of the FNA specimens in our institute are not sent for molecular studies, and cases with indeterminate cytology without subsequent operation are not included in this analysis. Second, although NTRK rearrangements have been reported mutually exclusive with BRAF V600E mutation in most of the series, 13,14,20 rare coexistence of these 2 molecular divers has been reported in 4 PTC cases previously. 15,28,29 In our testing algorithm, BRAF V600Epositive PTC was excluded as the initial step and was not tested for NTRK rearrangements.…”

“…13,14 The histologic features of NTRK-rearranged PTC, such as multinodular growth, mixed follicular and papillary patterns, and presence of solid areas, have been meticulously described in several previous studies. 10,11,[15][16][17][18][19][20] However, there were only 2 recent studies on the cytomorphologic features of NTRK-rearranged PTC. 21,22 Interestingly, a predominance of indeterminate cytologic diagnosis was highlighted by Abi-Raad et al 21 in 77% of the cases, whereas suspicious for malignancy or malignant was the most common cytologic diagnosis in up to 89% of the cases by Viswanathan et al 22 Some reported cytomorphologic characteristics were also inconsistent; for example, fibrotic fragments were frequently identified in 93% of the cases in the series by Viswanathan et al 22 but were unmentioned by Abi-Raad et al 21 whereas background lymphocytic thyroiditis was present in 75% of the cases by Abi-Raad et al 21 but none in the series by Viswanathan et al 22 These differences prompted us to investigate the distribution of The Bethesda System for Reporting Thyroid Cytopathology (TBS) categories of the fineneedle aspiration (FNA) of NTRK-rearranged PTCs compared to PTCs with other molecular drivers in our cohort and further analyze the detailed cytomorphologic features of these cases.…”

EML4–NTRK3 Fusion Cervical Sarcoma: A Case Report and Literature Review

“…In this study, we reported that NTRK3 overexpression may also be associated with CNS metastasis in cervical or uterine sarcomas. In addition, NTRK3 or NTRK1 fusion genes are associated with distant metastasis in thyroid carcinomas ( 6 ). Our study found no significant difference in metastases between the most common TPM3-NTRK1 fusion and other fusion types in cervical or uterine sarcomas.…”

“…Accumulating evidence has revealed that NTRK fusion leads to a continuous elevation or activation of these TRK proteins. Meanwhile, these TRK family members have been demonstrated to induce cancer cell growth and activate downstream signaling pathways, such as PI3K-Akt-mTOR, Ras-MAPK-ERK, and PLC-γ-Ca2 + -PKC, that potentially lead to tumorigenesis ( 2 – 6 ). These findings have highlighted the role of NTRK fusion in the malignancy progression, and NTRK fusion genes have been actively investigated as promising therapeutic targets ( 7 ).…”

A Comprehensive Risk Assessment and Stratification Model of Papillary Thyroid Carcinoma Based on the Autophagy-Related LncRNAs

“…The status of telomerase reverse transcriptase (TERT) mutation has been discovered to serve as an independent prognostic factor for PTC (25). NTRK, HRAS, KRAS, NRAS, RET, RET/PTC, and PAX8/PPARg gene mutations were proven as oncogenic driver mutations in tumorigenesis of PTC (26)(27)(28). The unique oncogene duet of coexisting BRAF V600E and TERT promoter mutations is widely proven to be a robust genetic background promoting thyroid cancer aggressiveness (29)(30)(31).…”