TERT aberrancies: a screening tool for malignancy in follicular thyroid tumours

Paulsson, Johan O.; Mu, Ninni; Shabo, Ivan; Wang, Na; Zedenius, Jan; Larsson, Catharina; Juhlin, Carl Christofer

doi:10.1530/erc-18-0050

Cited by 46 publications

(69 citation statements)

References 27 publications

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“…Compared with other clinicopathological features, the TERT promoter mutations possibly make more contribution to distant metastasis and advanced TNM stage of DTC, especially to distant metastasis of FTC (OR = 24.29). As described in nearly all the relevant literature on prognosis [16,20,26,67], our metaanalysis showed that TERT promoter mutations were strongly associated with persistence/recurrence, and disease-specific mortality, and indicated that patients with TERT promoter mutations in FTC also have poor prognosis. Thus, TERT promoter mutations may be considered biomarkers for prognosis in FTC.…”

Section: Discussionsupporting

confidence: 62%

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Association between TERT promoter mutations and clinical behaviors in differentiated thyroid carcinoma: a systematic review and meta-analysis

et al. 2019

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Background The association between telomerase reverse transcriptase (TERT) promoter mutations and some clinical behaviors in thyroid cancer remains controversial and requires additional investigation. This study aimed to evaluate the association between TERT promoter mutations and clinical behaviors (including clinicopathological features and prognosis) in differentiated thyroid carcinomas (DTC). Methods We performed an up-to-date systematic review and current comprehensive meta-analysis. We searched three electronic databases for relevant studies. We used fixedor random-effect models to calculate pooled estimated odds ratios (ORs) or standardized mean differences (SMDs) and corresponding 95% confidence intervals (CIs). Results We included 51 eligible studies incorporating 11,382 cases. Average frequencies of TERT promoter mutations in DTC, papillary (PTC), and follicular (FTC) thyroid carcinomas were 10.9%, 10.6%, and 15.1%, respectively. In DTC and PTC, TERT promoter mutations were significantly associated with sex, age, tumor size, vascular invasion, extrathyroidal extension, lymph node and distant metastases, advanced tumor, nodes, and metastasis (TNM) stage, persistence/recurrence, and disease-specific mortality. In FTC, TERT promoter mutations were significantly associated with age, distant metastases, advanced TNM stage, persistence/recurrence, and disease-specific mortality. Conclusions TERT promoter mutations could be considered as biomarkers assisting in risk stratification, prognostic prediction, and individualizing therapeutic options for DTC (PTC and FTC).

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Section: Discussionsupporting

confidence: 62%

“…In FTC, the average frequency of TERT promoter mutations was 15.1%, which was higher than that in PTC. The majority of the studies reported TERT promoter mutations were not detected in FTA [16,67,69,71]. However, a current case report study showed TERT promoter (C228T) mutation in a patient with FTA [70].…”

Section: Discussioncontrasting

confidence: 52%

Association between TERT promoter mutations and clinical behaviors in differentiated thyroid carcinoma: a systematic review and meta-analysis

et al. 2019

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“…Due to the unavailability of mRNA samples, we could not study directly the effects of CNV on TERT mRNA expression. However, other studies have shown the association between TERT copy number gain and mRNA expression in several cancer types, including FTC . Nevertheless, larger studies, particularly those focusing on advanced thyroid cancers, are required to provide definitive confirmation of this mechanism.…”

Section: Discussionmentioning

confidence: 97%

“…Reactivation of telomerase in human malignancies has also been linked to TERT amplification . In fact, the TERT gene locus was found to be amplified in various cancers including lung, breast, cervical carcinomas, and FTC, prompting us to examine the TERT gene for copy number alterations in different types of thyroid cancer. Interestingly, we observed that the increase in TERT locus copy number was more common in FTC, HCC, and PDTC, as compared to PTC.…”

Section: Discussionmentioning

confidence: 99%

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Spectrum of TERT promoter mutations and mechanisms of activation in thyroid cancer

2019

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Background Reactivation of telomerase reverse transcriptase (TERT) is an important event in cancer. Two hotspot mutations in the TERT promoter region, c.‐124C > T (C228T) and c.‐146C > T (C250T), occur in various cancer types including thyroid cancer. They generate de novo binding sites for E‐twenty‐six (ETS) transcription factors causing increased TERT transcription. The aim of this study was to search for novel TERT promoter mutations and additional mechanisms of TERT activation in thyroid cancer. Methods We studied 198 papillary thyroid carcinomas (PTCs), 34 follicular thyroid carcinomas (FTCs), 40 Hürthle cell carcinomas (HCCs), 14 poorly differentiated/anaplastic thyroid carcinomas (PDTC/ATC), and 15 medullary thyroid carcinomas (MTCs) for mutations in an −424 bp to +64 bp region of TERT. The luciferase reporter assay was used to functionally characterize the identified alterations. Copy number variations (CNVs) in the TERT region were analyzed using TaqMan copy number assay and validated with fluorescence in situ hybridization (FISH). Results We detected the hotspot c.‐124C > T and c.‐146C > T mutations in 7% PTC, 18% FTC, 25% HCC, and 86% PDTC/ATC. One PTC carried a c.‐124C > A mutation. Furthermore, we identified two novel mutations resulting in the formation of de novo ETS‐binding motifs: c.‐332C > T in one MTC and c.‐104_‐83dup in one PTC. These genetic alterations, as well as other detected mutations, led to a significant increase in TERT promoter activity when assayed using luciferase reporter system. In addition, 5% of thyroid tumors were found to have ≥3 copies of TERT. Conclusions This study confirms the increased prevalence of TERT promoter mutations and CNV in advanced thyroid cancers and describes novel functional alterations in the TERT gene promoter, including a point mutation and small duplication. These mutations, as well as TERT copy number alterations, may represent an additional mechanism of TERT activation in thyroid cancer.

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Facilitation of Definitive Cancer Diagnosis With Quantitative Molecular Assays of BRAF V600E and TERT Promoter Variants in Patients With Thyroid Nodules

Fu,

Chazen,

Monteiro

et al. 2023

JAMA Netw Open

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ImportanceMolecular testing of the presence of pathogenic genomic variants in a tumor without quantifying the variant allele fraction (VAF) does not differentiate the variation extent among tumors, often resulting in an inconclusive diagnosis because of interpatient variability.ObjectiveTo examine the association between the quantification of VAFs of BRAF V600E and TERT promoter variants and a definitive cancer diagnosis of thyroid tumors.Design, Setting, and ParticipantsThis diagnostic study analyzed a cohort of 378 surgically resected thyroid tumors with a maximum dimension of 1 cm or larger between March 15, 2016, and March 16, 2020, and a separate cohort of 217 residual thyroid fine-needle aspiration (FNA) biopsy specimens obtained from January 22, 2020, to March 2, 2021, at Mount Sinai Hospital, Toronto, Ontario, Canada. Data analysis was conducted between February 1, 2021, and February 1, 2023.ExposuresQuantitative VAF assays of BRAF V600E and TERT promoter variants (C228T and C250T) were performed by digital polymerase chain reaction molecular assays.Main Outcomes and MeasuresThe VAFs of BRAF V600E and TERT promoter variants were correlated with tumor histologic diagnoses and histopathologic features to delineate the association of VAF assays with tumor malignancy. The receiver operating characteristic curve analysis, sensitivity, specificity, positive predictive value, negative predictive value, and logistic regression analysis based on follow-up histopathologic types were used to determine the diagnostic utility of the quantitative molecular assays.ResultsA total of 595 specimens, including 378 surgically resected thyroid tumors and 217 thyroid nodule FNA biopsy specimens, were collected from 580 patients (436 [75.2%] female with a mean [SD] age of 50 [16] years and 144 [24.8%] male with a mean [SD] age of 55 [14] years). Sensitive VAF assays of 378 thyroid tumors revealed the presence of the BRAF V600E variant in 162 tumors (42.9%), with 26 (16.0%) at a low VAF of 1% or less and 136 (84.0%) at a high VAF of greater than 1%, and the presence of TERT promoter variants in 49 tumors (13.0%), including 45 C228T variants (91.8%), 15 (33.3%) of which were quantified as having a low VAF (≤1%) and 30 (66.7%) as having a high VAF (&gt;1%), and 4 C250T variants (8.2%) with VAFs between 40.0% and 47.0%. All tumors detected with BRAF V600E and/or TERT promoter variants, whether at low or high VAFs, received a definitive cancer diagnosis. Further analysis delineated a significant association between high VAFs of either variant individually or different VAF levels for both variants in coexistence and aggressive histopathologic features of tumors. Excluding low VAFs assisted in identifying patients at an intermediate-to-high risk of recurrence (odds ratio, 5.3; 95% CI, 1.9-14.6; P = .001). The VAF assays on the residual FNA biopsy specimens showed a high agreement to those on surgical tissues (κ = 0.793, P &lt; .001) and stratified malignancy in 40 of 183 indeterminate FNA cases (21.9%), with a sensitivity of 93.8% (95% CI, 67.7%-99.7%), specificity of 90.0% (95% CI, 75.4%-96.7%), positive predictive value of 78.9% (95% CI, 53.9%-93.0%), and negative predictive value of 97.3% (95% CI, 84.2%-99.9%).Conclusions and RelevanceThis diagnostic study suggests that sensitive quantitative VAF assays of BRAF V600E and TERT promoter variants can elucidate the interpatient variability in tumors and facilitate a definitive cancer diagnosis of thyroid nodules by differentiating the variation extent of genomic variants, even at low VAFs.

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TERT aberrancies: a screening tool for malignancy in follicular thyroid tumours

Cited by 46 publications

References 27 publications

Association between TERT promoter mutations and clinical behaviors in differentiated thyroid carcinoma: a systematic review and meta-analysis

Association between TERT promoter mutations and clinical behaviors in differentiated thyroid carcinoma: a systematic review and meta-analysis

Spectrum of TERT promoter mutations and mechanisms of activation in thyroid cancer

Facilitation of Definitive Cancer Diagnosis With Quantitative Molecular Assays of BRAF V600E and TERT Promoter Variants in Patients With Thyroid Nodules

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