Differences in Mutational Profile between Follicular Thyroid Carcinoma and Follicular Thyroid Adenoma Identified Using Next Generation Sequencing.

Martyna Borowczyk,Dorota Filipowicz,Frederik A Verburg,Ewelina Szczepanek-Parulska,Katarzyna Ziemnicka,Barbara Więckowska,Bartłomiej Budny,Szymon Dębicki,Lidia Gil,Małgorzata Janicka-Jedyńska,Marek Ruchała

doi:10.3390/ijms20133126

Abstract

We aimed to identify differences in mutational status between follicular thyroid adenoma (FTA) and follicular thyroid cancer (FTC). The study included 35 patients with FTA and 35 with FTC. DNA was extracted from formalin-fixed paraffin-embedded (FFPE) samples from thyroidectomy. Next-generation sequencing (NGS) was performed with the 50-gene Ion AmpliSeq Cancer Hotspot Panel v2. Potentially pathogenic mutations were found in 14 (40%) FTA and 24 (69%) FTC patients (OR (95%CI) = 3.27 (1.22−8.75)). The number of mutations was higher in patients with FTC than FTA (p-value = 0.03). SMAD4 and STK11 mutations were present only in patients with FTA, while defects in FBXW7, JAK3, KIT, NRAS, PIK3CA, SMARCB1, and TP53 were detected exclusively in FTC patients. TP53 mutations increased the risk of FTC; OR (95%CI) = 29.24 (1.64–522.00); p-value = 0.001. FLT3-positivity was higher in FTC than in the FTA group (51.4% vs. 28.6%; p-value = 0.051). The presence of FLT3 and TP53 with no RET mutations increased FTC detectability by 17.1%, whereas the absence of FLT3 and TP53 with a presence of RET mutations increased FTA detectability by 5.7%. TP53 and FLT3 are candidate markers for detecting malignancy in follicular lesions. The best model to predict FTA and FTC may consist of FLT3, TP53, and RET mutations considered together.

Highlights

The differentiation between follicular thyroid adenoma (FTA) and follicular thyroid carcinoma (FTC) in preoperative diagnostics is not reliable when based on imaging or biopsy [1]
The molecular analyses allowed for the identification of at least one possibly pathogenic mutation in 14 out of 35 (40.0%) patients diagnosed with FTA and 24 (68.6%) out of 35 patients diagnosed with FTC (Table 1)
The number of detected mutations was significantly higher in patients with FTC in comparison with those diagnosed with FTA (p-value = 0.03)

Summary

Introduction

The differentiation between follicular thyroid adenoma (FTA) and follicular thyroid carcinoma (FTC) in preoperative diagnostics is not reliable when based on imaging or biopsy [1]. A main area on which research has focused is the identification of genetic alterations that may be present in FTC, but not in FTA. While in papillary thyroid cancer (PTC), next-generation sequencing (NGS) has yielded promising results [6,7], this technique has, far, rarely been applied to FTC [8]. The majority of studies in FTC have tested only well-recognized thyroid cancer-related genes using, e.g., a 7-gene [9], 24-gene panel, or standard PCR for single mutations [10]. To the best of our knowledge, authors comparing the genetic background of FTA and FTC have so far rarely applied NGS [12], which enables detection of many genetic changes simultaneously [13] and the analysis of the complex genetic interplay of distinct mutations [14]

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Conclusion