Highly prevalent BRAF V600E and low-frequency TERT promoter mutations underlie papillary thyroid carcinoma in Koreans

Abstract

Background: The presence of telomerase reverse transcriptase (TERT) promoter mutations have been associated with a poor prognosis in patients with papillary thyroid carcinomas (PTC). The frequency of TERT promoter mutations varies widely depending on the population and the nature of the study.

Methods: Data were prospectively collected in 724 consecutive patients who underwent thyroidectomy for PTC from 2018 to 2019. Molecular testing for BRAF V600E and TERT promoter mutations was performed in all cases.

Results: TERT promoter alterations in two hotspots (C228T and C250T) and C216T were found in 16 (2.2%) and 4 (0.6%) of all PTCs, respectively. The hotspot mutations were significantly associated with older age at diagnosis, larger tumor size, extrathyroidal extension, higher pathologic T category, lateral lymph node metastasis, and higher American Thyroid Association recurrence risk. The patients with C216T variant were younger and had a lower American Thyroid Association recurrence risk than those with hotspot mutations. Concurrent BRAF V600E was found in 19 of 20 cases with TERT promoter mutations. Of 518 microcarcinomas measuring ≤1.0 cm in size, hotspot mutations and C216T variants were detected in five (1.0%) and three (0.6%) cases, respectively.

Conclusions: Our study indicates a low frequency of TERT promoter mutations in Korean patients with PTC and supports previous findings that TERT promoter mutations are more common in older patients with unfavorable clinicopathologic features and BRAF V600E. TERT promoter mutations in patients with microcarcinoma are uncommon and may have a limited role in risk stratification. The C216T variant seems to have no clinicopathologic effect on PTC.

Keywords: BRAF; Molecular typing; Mutation rate; Papillary thyroid carcinoma; TERT promoter.

Fig. 1.

Schematic figure of the telomerase reverse transcriptase (TERT) promoter region and sequencing electropherograms of two hotspot mutations (C228T and C250T) and a C216T variant in the TERT promoter. The hotspot mutations resulted from a cytosine-to-thymine transition at genomic loci Chr5:1,295,228 (C228T) and 1,295,250 (C250T), respectively. The C216T variant is a cytosine-to-thymine transition at the 1,295,216 position of Chr5.

Fig. 2.

A pie chart depicting a portion of BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutations (C228T and C250T) in relation to histologic variants of papillary thyroid carcinoma (n=724). The middle and inner circles show the frequency of BRAF V600E and TERT promoter mutations, respectively. The other variants included eight diffuse sclerosing, eight oncocytic, five solid, three hobnail, and one cribriform-morular variant. TCF, tall cell features.