Differentiation of Follicular Thyroid Adenoma from Carcinoma by Means of Gene Expression Profiling with Adapter-Tagged Competitive Polymerase Chain Reaction

Abstract

Objective: Since preoperative differentiation between follicular thyroid adenoma (FTA) and carcinoma (FTC) remains very difficult, the purpose of this study was to identify the genes differentially expressed in FTA and FTC in order to construct a diagnostic system based on such genes for differentiation of FTA and FTC. Methods:Gene expression profiles of 45 FTAs and 22 FTCs were analyzed by means of adapter-tagged competitive polymerase chain reaction (ATAC-PCR) with 2,516 genes (learning set). The genes differentially expressed in FTAs and FTCs were then used to construct a diagnostic system based on the weighted-voting algorithm. In addition, a validation study of this diagnostic system was conducted using 12 FTAs and 6 FTCs (validation set). Results: The diagnostic system for differentiation of FTA and FTC, constructed with the aid of the learning set samples, was based on 60 genes differentially expressed in FTA and FTC, which included several genes previously identified as overexpressed in FTC (DPP4, KRT19 and IGFBP3) or FTA (trefoil factor 3 and thyroid peroxidase).The leave-one-out cross-validation study showed that the accuracy of this diagnostic system was as high as 90% (sensitivity: 77.3% and specificity: 95.6%), and was confirmed by the validation study (diagnostic accuracy: 83.3%; 95% confidence interval: 62.8–95.4%, sensitivity: 66.7% and specificity: 91.2%). Conclusions: This diagnostic system using the ATAC-PCR assay is expected to be clinically useful for preoperative differentiation between FTA and FTC since ATAC-PCR can be used for the small amount of RNA obtained from fine needle aspiration biopsy.

Trefoil Factor 3 (TFF3): A Promising Indicator for Diagnosing Thyroid Follicular Carcinoma

“…However, while other markers failed to show reproducible results in follow-up studies, researches at other institutes revealed the utility of TFF3 mRNA for the diagnosis of follicular carcinoma [32][33][34][35]. In 2005, Taniguchi et al used a unique system for analysis of gene expression called Adapter-Tagged Competitive PCR, to screen over 2000 genes expressed in thyroid follicular tumors and concluded that TFF3 mRNA is one of the most promising markers for diagnosing follicular carcinoma [32].…”

“…In 2005, Taniguchi et al used a unique system for analysis of gene expression called Adapter-Tagged Competitive PCR, to screen over 2000 genes expressed in thyroid follicular tumors and concluded that TFF3 mRNA is one of the most promising markers for diagnosing follicular carcinoma [32]. In 2007, Foukakis et al reevaluated 26 previously reported candidate genes and found that the combination of TFF3 and hTERT mRNA could most efficiently distinguish follicular carcinomas from adenomas [33].…”

“…Considering these facts, the discrepancy between pathological and TFF3-based diagnosis may be at least in part due to the difficulty in diagnosis of minimally invasive follicular carcinoma. Taniguchi et al provided evidence to support this hypothesis [32]. They chose 60 genes that were differentially expressed between follicular adenomas and carcinomas, and searched for combinations of genes that could diagnose follicular carcinoma with high accuracy.…”

Measurement of <i>TFF3</i> mRNA in aspirates from thyroid nodules using mesh filtration: The first clinical trial in 130 cases

“…Taniguchi et al measured the expression levels of more than 2500 genes expressed in follicular tumors and they examined whether the expression level of any genes or any set of genes could distinguish follicular carcinomas from adenomas. However, the accuracy never exceeded 90% even when they used a combination of the top 60 genes [10]. This study clearly indicated that at least 10% of the pathological diagnoses of follicular tumors do not correctly reflect their biological characteristics.…”

“…In the follow-up studies, many researchers at other institutes confirmed the utility of TFF3 mRNA in diagnosing follicular carcinoma [10][11][12][13][14][15][16][17]. A more intriguing property of TFF3 mRNA is that papillary and anaplastic thyroid carcinomas also show low T/G ratios [9,18].…”