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

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.

Molecular genetic markers of highly differentiated thyroid cancer (literature review and personal observations)

“…NRAS mutations are targets of the PI3K/AKT signalling pathway. However, they are considered only as precursors; further mutations are required for carcinogenesis, especially in follicular carcinoma and follicular variant papillary thyroid cancer [53]. There is also evidence of a positive correlation between RAS mutations and distant metastatic disease and a reduced survival rate in highly differentiated carcinoma [49].…”

Indeterminate Thyroid Nodules: From Cytology to Molecular Testing

“…They identified 12 deregulated miRNAs between RAS -mutated and RAS -negative FAs. Additionally, in the comparison between benign and malignant tumors positive for RAS mutations, three particular miRNAs of interest emerged: miR-146b-5p , which showed increasing upregulation from benign nodules to RAS -positive malignant nodules (i.e., miR-144-3p and miR-451a) , which were downregulated in malignant RAS -mutated tumors [ 51 ].…”