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Oncotarget. 2016 Oct 25;7(43):69638-69648. doi: 10.18632/oncotarget.11922.

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

Author information

1
Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
2
Department of Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, Korea.
3
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
4
Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
5
Department of General Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea.
6
Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea.

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.

KEYWORDS:

copy number alteration; follicular thyroid adenoma; follicular thyroid carcinoma; mutations; tumor progression

PMID:
27626165
PMCID:
PMC5342504
DOI:
10.18632/oncotarget.11922
[Indexed for MEDLINE]
Free PMC Article

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