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The distinction between follicular thyroid carcinomas (FTCs) and follicular-patterned benign lesions is almost impossible on fine-needle aspiration cytology. Furthermore, minimally invasive FTCs (MI-FTCs) with less than 4 vascular invasion foci generally have an excellent prognosis, but there are exceptions and, so far, no molecular marker appears able to identify them reliably. We aimed to distinguish benign lesions from low- and high-risk FTCs by a small-scale combination of genes. The expression analysis of 75 selected genes was performed on 18 follicular adenomas (FAs), 14 MI-FTCs and 6 widely invasive FTC (WI-FTCs). The mutational status of the RAS genes, TERT promoter and PAX8-PPARG rearrangements was also investigated. Seven samples were mutated, namely 3 MI-FTCs and 4 WI-FTCs. Twenty-five genes were differentially expressed (FDR &lt;0.05) between FAs and WI-FTCs. Six of these ( ECM1 , RXRG , SDPR , SLC26A4 , TIFF3 , TIMP1 ) were also differently expressed among MI-FTCs and FAs or WI-FTCs and were considered to build a classification model, which was tested to classify samples according to their histological class. Hence, 31 out of 38 were correctly classified, and accuracy remained high after cross-validation (27/38). The 2 MI-FTCs incorrectly classified as WI-FTCs harbored both RAS and TERT promoter mutations. The capability of these six genes to stratify benign, low- and high-risk lesions appears to be promising in supporting the diagnosis of indeterminate thyroid nodules.

A six-gene panel to label follicular adenoma, low- and high-risk follicular thyroid carcinoma