Mutational burdens and evolutionary ages of thyroid follicular adenoma are comparable to those of follicular carcinoma.

Seung-Hyun Jung,Chan Kwon Jung,Min Sung Kim,Hyun-Chun Park,Tae-Min Kim,So Youn Kim,Sung Hak Lee,Yeun-Jun Chung,Sug Hyung Lee,Jieying Liu,Ja-Seong Bae

doi:10.18632/oncotarget.11922

Abstract

Follicular thyroid adenoma (FTA) precedes follicular thyroid carcinoma (FTC) by definition with a favorable prognosis compared to FTC. However, the genetic mechanism of FTA to FTC progression remains unknown. For this, it is required to disclose FTA and FTC genomes in mutational and evolutionary perspectives. We performed whole-exome sequencing and copy number profiling of 14 FTAs and 13 FTCs, which exhibited previously-known gene mutations (NRAS, HRAS, BRAF, TSHR and EIF1AX) and copy number alterations (CNAs) (22q loss and 1q gain) in follicular tumors. In addition, we found eleven potential cancer-related genes with mutations (EZH1, SPOP, NF1, TCF12, IGF2BP3, KMT2C, CNOT1, BRIP1, KDM5C, STAG2 and MAP4K3) that have not been reported in thyroid follicular tumors. Of note, FTA genomes showed comparable levels of mutations to FTC in terms of the number, sequence composition and functional consequences (potential driver mutations) of mutations. Analyses of evolutionary ages using somatic mutations as molecular clocks further identified that FTA genomes were as old as FTC genomes. Whole-transcriptome sequencing did not find any gene fusions with potential significance. Our data indicate that FTA genomes may be as old as FTC genomes, thus suggesting that follicular thyroid tumor genomes during the transition from FTA to FTC may stand stable at genomic levels in contrast to the discernable changes at pathologic and clinical levels. Also, the data suggest a possibility that the mutational profiles obtained from early biopsies may be useful for the molecular diagnosis and therapeutics of follicular tumor patients.

Highlights

Thyroid cancer is the most common endocrine malignancy worldwide
Our data indicate that Follicular thyroid adenoma (FTA) genomes may be as old as follicular thyroid carcinoma (FTC) genomes, suggesting that follicular thyroid tumor genomes during the transition from FTA to FTC may stand stable at genomic levels in contrast to the discernable changes at pathologic and clinical levels
In addition to copy number alterations (CNAs), we found that one FTC harbored copy-neutral loss of heterozygosity (LOH) event on 9p24.3-p13.1 (Figure 2D), which had been reported in FTC [21]

Summary

Introduction

Thyroid cancers consist of papillary (75–85%), follicular (10–20%), medullary (~5%) and anaplastic carcinomas (< 5%) [1, 2]. Follicular thyroid carcinoma (FTC) has relatively worse clinical courses than papillary thyroid carcinoma (PTC) with frequent hematogenous spread and recurrence [1]. FTA and FTC fall within a biologic continuum and capsular invasion and/or www.impactjournals.com/oncotarget vascular invasion status are gold standards for distinction between FTA and FTC [1, 6]. In this scenario, FTA originated from the thyroid follicle penetrates the tumor capsule and eventually progresses to FTC.

Methods

Results

Conclusion