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

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.

SUBMITTER: Rusinek D

PROVIDER: S-EPMC7352936 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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<i>TERT</i> Promoter Mutations and Their Impact on Gene Expression Profile in Papillary Thyroid Carcinoma.

Rusinek Dagmara D Pfeifer Aleksandra A Cieslicka Marta M Kowalska Malgorzata M Pawlaczek Agnieszka A Krajewska Jolanta J Szpak-Ulczok Sylwia S Tyszkiewicz Tomasz T Halczok Monika M Czarniecka Agnieszka A Zembala-Nozynska Ewa E Chekan Mykola M Lamch Roman R Handkiewicz-Junak Daria D Ledwon Aleksandra A Paliczka-Cieslik Ewa E Kropinska Aleksandra A Jarzab Barbara B Oczko-Wojciechowska Malgorzata M

Cancers 20200617 6

<h4>Background</h4>Telomerase reverse transcriptase promoter (<i>TERT</i>p) 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 <i>TERT</i>p mutations in PTC was the aim of our study.<h4>Methods</h4>The studied cohort consisted of 54 PTCs, among them 24 cases with distant metastases. <i>BRAF</i> V600E, <i> ...[more]

PMID: 32560331

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Project description:BackgroundTwo recurrent TERT (telomerase reverse transcriptase) promoter mutations, C228T and C250T, have been reported in thyroid carcinomas and were correlated with high-risk clinicopathological features and a worse prognosis. Although far more frequent in the poorly differentiated and undifferentiated thyroid cancer, the TERT promoter mutations play a significant role on PTC recurrence and disease-specific mortality. However, the prevalence varies considerably through studies and it is uncertain if these differences are due to population variation or the methodology used to detect TERT mutations. In this study we aim to compare three different strategies to detect TERT promoter mutations in PTC.MethodsDNA was isolated from formalin-fixed paraffin-embedded (FFPE) specimens from 89 PTC and 40 paired lymph node metastases. The prevalence of the hot spot TERT C228T and C250T mutations was assessed in FFPE samples using TaqMan SNP genotyping assays. Random samples were tested by Sanger Sequencing and droplet digital PCR (ddPCR).ResultsIn general, 16 out of 89 (18%) PTC samples and 14 out of 40 (35%) lymph node metastases harbored TERT promoter mutations by TaqMan assay. Sanger sequencing, performed in random selected samples, failed to detect TERT mutations in four samples that were positive by TaqMan SNP genotyping assay. Remarkably, ddPCR assay allowed detection of TERT promoter mutations in six samples that harbor very low mutant allele frequency (≤ 2%) and were negative by both genotype assay and Sanger Sequencing.ConclusionThis study observed a good concordance among the methodologies used to detect TERT promoter mutations when a high percentage of mutated alleles was present. Sanger analysis demonstrated a limit of detection for mutated alleles. Therefore, the prevalence of TERT promoter mutations in PTC may be higher than previously reported, since most studies have conventionally used Sanger sequencing. The efficient characterization of genetic alterations that are used as preoperative or postoperative diagnostic, risk stratification of the patient and individualized treatment decisions, mainly in highly heterogeneous tumors, require highly sensitive and specific approaches.

Dataset Information

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

Publications

<i>TERT</i> Promoter Mutations and Their Impact on Gene Expression Profile in Papillary Thyroid Carcinoma.

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