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. 2020 Jun 17;12(6):1597.
doi: 10.3390/cancers12061597.

TERT Promoter Mutations and Their Impact on Gene Expression Profile in Papillary Thyroid Carcinoma

Dagmara Rusinek  1 , Aleksandra Pfeifer  1 , Marta Cieslicka  1 , Malgorzata Kowalska  1 , Agnieszka Pawlaczek  1 , Jolanta Krajewska  2 , Sylwia Szpak-Ulczok  2 , Tomasz Tyszkiewicz  1 , Monika Halczok  1 , Agnieszka Czarniecka  3 , Ewa Zembala-Nozynska  4 , Mykola Chekan  4 , Roman Lamch  4 , Daria Handkiewicz-Junak  2 , Aleksandra Ledwon  2 , Ewa Paliczka-Cieslik  2 , Aleksandra Kropinska  2 , Barbara Jarzab  2 , Malgorzata Oczko-Wojciechowska  1
Affiliations

TERT Promoter Mutations and Their Impact on Gene Expression Profile in Papillary Thyroid Carcinoma

Dagmara Rusinek et al. Cancers (Basel). .

Abstract

Background: Telomerase reverse transcriptase promoter (TERTp) mutations are related to a worse prognosis in various malignancies, including papillary thyroid carcinoma (PTC). Since mechanisms responsible for the poorer outcome of TERTp(+) patients are still unknown, searching for molecular consequences of TERTp mutations in PTC was the aim of our study.

Methods: The studied cohort consisted of 54 PTCs, among them 24 cases with distant metastases. BRAF V600E, RAS, and TERTp mutational status was evaluated in all cases. Differences in gene expression profile between TERTp(+) and TERTp(-) PTCs were examined using microarrays. The evaluation of signaling pathways and gene ontology was based on the Gene Set Enrichment Analysis.

Results: Fifty-nine percent (32/54) of analyzed PTCs were positive for at least one mutation: 27 were BRAF(+), among them eight were TERTp(+), and 1 NRAS(+), whereas five other samples harbored RAS mutations. Expression of four genes significantly differed in BRAF(+)TERTp(+) and BRAF(+)TERTp(-) PTCs. Deregulation of pathways involved in key cell processes was observed.

Conclusions: TERTp mutations are related to higher PTC aggressiveness. CRABP2 gene was validated as associated with TERTp mutations. However, its potential use in diagnostics or risk stratification in PTC patients needs further studies.

Keywords: TERT; gene expression profile; papillary thyroid carcinoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
PCA analysis of PTCs with reference to BRAF, TERTp and RAS mutational status.
Figure 2
Figure 2
Analysis of BRS (A) and TDS (B). High BRS depicts RAS-like, whereas low BRS depicts BRAF-like samples. High TDS depicts high expression of thyroid specific genes and high thyroid differentiation. TDS: The Thyroid Differentiation Score, BRS: the BRAF-like RAS-like Score. p-values shown on plots were calculated with Kruskal-Wallis and two-tailed Mann-Whitney tests.
Figure 3
Figure 3
TERT gene expression in PTC sets with different mutations; RAS(+) cohort was BRAF(−) and TERTp(−). p-values shown on plot were calculated with Kruskal-Wallis and two-tailed Mann-Whitney tests.
Figure 4
Figure 4
Expression of four genes significantly differentiating BRAF(+)TERTp(+) and BRAF(+)TERTp(−) PTCs in all analyzed PTC cases; RAS(+) cohort was BRAF(−) and TERTp(−). p-values shown on plots were calculated with Kruskal-Wallis and two-tailed Mann-Whitney tests.
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