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. 2023 Aug;46(8):1651-1662.
doi: 10.1007/s40618-023-02023-5. Epub 2023 Feb 7.

MicroRNA expression profiling of RAS-mutant thyroid tumors with follicular architecture: microRNA signatures to discriminate benign from malignant lesions

E Macerola  1 , A M Poma  1 , P Vignali  1 , A Proietti  1 , L Torregrossa  1 , C Ugolini  1 , A Basolo  2 , A Matrone  2 , R Elisei  2 , F Santini  2 , F Basolo  3
Affiliations

MicroRNA expression profiling of RAS-mutant thyroid tumors with follicular architecture: microRNA signatures to discriminate benign from malignant lesions

E Macerola et al. J Endocrinol Invest. 2023 Aug.

Abstract

Purpose: RAS mutations represent common driver alterations in thyroid cancer. They can be found in benign, low-risk and malignant thyroid tumors with follicular architecture, which are often diagnosed as indeterminate nodules on preoperative cytology. Therefore, the detection of RAS mutations in preoperative setting has a suboptimal predictive value for malignancy. In this study, we investigated differentially expressed microRNA (miRNA) in benign and malignant thyroid tumors with follicular architecture carrying mutations in RAS genes.

Methods: Total RNA was purified from 60 RAS-mutant follicular-patterned thyroid tumors, including follicular adenoma (FA), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), papillary and follicular thyroid carcinoma cases (PTC, FTC); 22 RAS-negative FAs were used as controls. The expression analysis of 798 miRNAs was performed by digital counting (nCounter nanoString platform).

Results: Comparing RAS-mutant and RAS-negative FAs, 12 miRNAs showed significant deregulation, which was likely related to the oncogenic effects of RAS mutations. Twenty-two miRNAs were differentially expressed in RAS-mutant benign versus malignant tumors. Considering the tumor type, 24 miRNAs were deregulated in PTC, 19 in NIFTP, and seven in FTC and compared to FA group; among these, miR-146b-5p, miR-144-3p, and miR-451a showed consistent deregulation in all the comparisons with the highest fold change.

Conclusions: The miRNA expression analysis of follicular-patterned thyroid tumors demonstrated that RAS mutations influences miRNA profile in benign tumors. In addition, several miRNAs showed a histotype-specific deregulation and could discriminate between RAS-mutant benign and RAS-mutant malignant thyroid lesions, thus deserving further investigation as potential diagnostic markers.

Keywords: Follicular-patterned tumors; Molecular markers; RAS mutations; Thyroid cancer; microRNA.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Heatmaps representing the unsupervised clustering of miRNAs and samples. a All samples were included (n = 82), b only RAS-mutant samples were included (n = 60). Each row represents one miRNA, each column one sample, the colors indicate high (red) and low (blue) gene expression level. Colored sidebars represent mutational status, histological diagnosis, and benign or malignant neoplasm, as it is indicated in the legend
Fig. 2
Fig. 2
a, b Principal component analysis of all samples, including RAS-negative FAs (n = 82), labeled for mutational status and histological class. c, d Principal component analysis of the 60 RAS-mutant tumors, tumors are shown with different colors according to the involved RAS gene (NRAS, HRAS, KRAS) and to the histological class
Fig. 3
Fig. 3
a Venn diagram representing the number of significantly deregulated miRNAs in different histological classes. b–d Volcano plots showing the relative expression (logFC) of miRNAs in PTC, NIFTP, and FTC classes compared to FA group. MiRNAs have been highlighted based on their expression level (green for logFC >|1|), significance level (light blue for P value ≤ 0.05), or both (orange for miRNAs showing logFC >|1| and P value ≤ 0.05). FTC follicular thyroid carcinoma, NIFTP noninvasive follicular thyroid neoplasm with papillary-like nuclear features, PTC papillary thyroid carcinoma, FA follicular adenoma, NS not significant, Log2 FC base 2 logarithm of the fold change
Fig. 4
Fig. 4
a–c Relative expression levels of miR-146b-5p, miR-144-3p, and miR-451a (expressed in log2FC) in all the histological classes. d ROC analysis showing the diagnostic performance of the three selected miRNAs. FA WT wild-type follicular adenoma, FA follicular adenoma, NIFTP noninvasive follicular thyroid neoplasm with papillary-like nuclear features, FTC follicular thyroid carcinoma, PTC papillary thyroid carcinoma
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