Mutation profiles of follicular thyroid tumors by targeted sequencing

Huanli Duan,Hui Zhang,Huanwen Wu,Xiaoding Liu,Zhiyong Liang,Xinyu Ren

doi:10.1186/s13000-019-0817-1

Abstract

BackgroundOne of the major challenges remaining in the classification of thyroid tumor is the determination of whether a nodule is benign or malignant. We aimed to characterize the mutational profiles of follicular thyroid tumor and to identify markers with potential diagnostic and prognostic implications.MethodsTargeted sequencing with a panel of 18 thyroid cancer-related genes was performed on 48 tissue samples from follicular thyroid adenoma (FTA), 32 follicular tumors of uncertain malignant potential (FT-UMP), 17 well-differentiated tumors of uncertain malignant potential (WDT-UMP) and 53 samples from follicular thyroid carcinoma (FTC). The correlation of mutation profiles and clinicopathological features and prognosis were also analyzed.ResultsWe identified 95 nonsilent mutations spanning 14 genes. Specifically, TERT promoter (TERTp) mutations were exclusively detected in FTC. A total of 80% EIF1AX exon 2 mutations (4/5) and 75% TSHR mutations (3/4) occurred in FTA, whereas the rest of them occurred in FT-UMP. KRAS mutations and TP53 mutations were only presented in borderline or malignant tumors. H/N-RAS mutations were detected in all four subtypes, but were most commonly found in WDT-UMP (p = 0.031). All N-RAS mutations were located at codon 61. BRAF V600E and RET fusion were absent in the entire cohort. In FTC cases, EIF1AX mutations were all located at intron 5/exon 6 and correlated with advanced disease (p = 0.032). Both EIF1AX and TERTp mutations predicted shorter disease-free survival (p = 0.007, p = 0.024, respectively). Further analysis revealed that TERTp mutations were correlated with shorter disease-free survival in patients with minimally invasive /encapsulated angioinvasive FTC (p = 0.017), but not in those with widely invasive FTC (p = 0.297).ConclusionTERTp, EIF1AX, TSHR, H/N/K-RAS and TP53 mutations may have diagnostic or prognostic potential in follicular thyroid tumors. TERTp mutations may predict a poor outcome in patients with minimally invasive/encapsulated angioinvasive FTC.

Highlights

One of the major challenges remaining in the classification of thyroid tumor is the determination of whether a nodule is benign or malignant
As one of the categories, follicular thyroid carcinoma (FTC) is a high-risk cancer with the likelihood of distant relapse [1].FTC is the malignant counterpart of follicular thyroid adenoma (FTA), the latter commonly found as benign neoplasm of the thyroid gland
Study cases One hundred and fifty-three cases initially diagnosed as FTA, atypical follicular thyroid adenoma (AFTA) and FTC between June 2010 and May 2015 were derived from the database of the Department of Pathology, Peking Union Medical College Hospital

Summary

Introduction

One of the major challenges remaining in the classification of thyroid tumor is the determination of whether a nodule is benign or malignant. We aimed to characterize the mutational profiles of follicular thyroid tumor and to identify markers with potential diagnostic and prognostic implications. The most common type of endocrine malignancy, predominantly arises from thyroid follicular cells, with approximately 95% being differentiated thyroid cancer. Numerous studies have shown that TERTp mutations were more popular in advanced thyroid cancers and strongly correlated with poor clinical outcomes [6,7,8, 13]. EIF1AX gene was recently identified as a new thyroid cancer-related gene. Distinct mutations on EIF1AX may be correlated with different tumor phenotypes [15]. The role of TERTp or EIF1AX mutations in follicular thyroid tumors hadn’t been fully investigated

Objectives

Methods

Results

Conclusion