MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility

Abstract

Objective: MicroRNA (miRNA) expression is deregulated in many types of human cancers. We sought to investigate the expression patterns of miRNA in all major types of thyroid tumors, including tumors carrying distinct oncogenic mutations, and to explore the utility of miRNA profiling for the preoperative diagnosis of thyroid nodules.

Design: miRNA expression levels were detected in 60 surgically removed thyroid neoplastic and nonneoplastic samples and in 62 fine-needle aspiration (FNA) samples by RT-PCR using TaqMan MicroRNA Panel or individual miRNA sequence-specific primers. miRNA expression levels were calculated relative to normal thyroid tissue. All tumors were genotyped for most common mutations.

Results: Various histopathological types of thyroid tumors, including those deriving from the same cell type, showed significantly different profiles of miRNA expression. Oncocytic tumors, conventional follicular tumors, papillary carcinomas, and medullary carcinomas formed distinct clusters on the unsupervised hierarchical clustering analysis. Significant correlation between miRNA expression patterns and somatic mutations was observed in papillary carcinomas. A set of seven miRNAs (miR-187, miR-221, miR-222, miR-146b, miR-155, miR-224, and miR-197) that were most differentially overexpressed in thyroid tumors vs. hyperplastic nodules in the surgical samples was validated in the FNA samples, showing high accuracy of thyroid cancer detection.

Conclusions: In this study, we demonstrate that various histopathological types of thyroid tumors have distinct miRNA profiles, which further differ within the same tumor type, reflecting specific oncogenic mutations. A limited set of miRNAs can be used diagnostically with high accuracy to detect thyroid cancer in the surgical and preoperative FNA samples.

Figure 1

Cluster dendrogram of miRNA expression of thyroid tumors showing four major clusters: oncocytic FC (OFC) and FA (OFA), conventional FC (CFC) and FA (CFA), PC, and MC.

Figure 2

Cluster dendrogram of miRNA expression in thyroid tumors with different mutations.

Figure 3

A, Expression levels of selected miRNAs in PCs with various mutations (mean ± se); B, PCA of log-transformed data for all mutational group probe sets. Blue, BRAF mutants; green, RAS mutants; red, RET/PTC mutants; yellow, tumors with no mutation.

Figure 4

A, Expression levels of selected miRNAs in various types of thyroid cancer based on the analysis of surgically removed tumors (mean ± se); B, expression of selected miRNAs in thyroid preoperative FNA samples from patients who subsequently underwent surgery. The surgical pathology diagnoses are shown at the bottom. CFC, Conventional FC; HN, hyperplastic nodules; OFC, oncocytic FC.