Prognostic implication of <scp>BRAF</scp> and <scp>TERT</scp> promoter mutation combination in papillary thyroid carcinoma—A meta‐analysis

Vuong, Huy Gia; Altibi, Ahmed; Duong, Uyen; Hassell, Lewis

doi:10.1111/cen.13413

Cited by 117 publications

(78 citation statements)

References 28 publications

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“…In GBM, TERTp mutations coexist with EGFR amplification [64,77,111], and in urothelial bladder carcinoma, they are associated with FGFR3 (Fibroblast Growth Factor Receptor 3) mutations [61,94]. In~50% of melanoma, urothelial, and thyroid cancers, TERTp mutations coexist with the common BRAF-V600E mutation [52,88,89,105,106,108,116,152]. GFR and BRAF/RAS kinases control the MAPK and PI3K-Akt pathways that lead to cell growth, survival, and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

The Solo Play of TERT Promoter Mutations

Hafezi

Perez-Bercoff

2020

Cells

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The reactivation of telomerase reverse transcriptase (TERT) protein is the principal mechanism of telomere maintenance in cancer cells. Mutations in the TERT promoter (TERTp) are a common mechanism of TERT reactivation in many solid cancers, particularly those originating from slow-replicating tissues. They are associated with increased TERT levels, telomere stabilization, and cell immortalization and proliferation. Much effort has been invested in recent years in characterizing their prevalence in different cancers and their potential as biomarkers for tumor stratification, as well as assessing their molecular mechanism of action, but much remains to be understood. Notably, they appear late in cell transformation and are mutually exclusive with each other as well as with other telomere maintenance mechanisms, indicative of overlapping selective advantages and of a strict regulation of TERT expression levels. In this review, we summarized the latest literature on the role and prevalence of TERTp mutations across different cancer types, highlighting their biased distribution. We then discussed the need to maintain TERT levels at sufficient levels to immortalize cells and promote proliferation while remaining within cell sustainability levels. A better understanding of TERT regulation is crucial when considering its use as a possible target in antitumor strategies.Cells 2020, 9, 749 2 of 28 by copy number variants (CNV), TERT or TERTp structural variants, chromosomal rearrangements juxtaposing TERTp to enhancer elements, cellular and viral oncogenes such as Hepatitis B virus (HBV) X protein (HBx) or high-risk Human papillomavirus (HPV)16 and HPV18 E6 oncoprotein, and, last but not least, mutations within TERTp (31% of TERT-expressing cancers) ( Figure 1A) [10, 30-38] (reviewed in [3,4,9,18-20,39]). Increased TERTp methylation is typically recorded in >50% of TERT-expressing tumors and cell lines [10,[40][41][42][43][44][45][46][47]. Epigenetic regulation of TERTp is based on altered methylation patterns of specific regions. Hypomethylation of the region between −200 and −100 from the Translational Start site (TSS), encompassing the core promoter, enables binding of c-Myc and Sp-1, thus reactivating transcription. In contrast, the region spanning exon 1 (positions +1 to ±100 from the TSS) contains a binding site for the DNA insulator CTCF. Hypermethylation of this region disrupts binding of CTCF and therefore allows TERT transcription [41][42][43][44]. Similarly, the region between −600 and −200 from the TSS contains a second CTCF binding site and is partially hypermethylated in TERT-expressing cells [41][42][43][44].

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Section: Discussionmentioning

confidence: 99%

The Solo Play of TERT Promoter Mutations

Hafezi

Perez-Bercoff

2020

Cells

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“…Risk of persistent or recurrent disease. Table 3 summarises the system developed in 2015 by the American Thyroid Association (ATA) to estimate the risk of persistent or recurrent TC based on data available shortly after treatment of the primary cancer [8,[24][25][26]. These criteria have now been revised and refined based on emerging evidence.…”

Section: Staging and Risk Assessmentmentioning

confidence: 99%

“…The BRAF V600E mutation is associated with aggressive histologic features, lymph node metastases and ETE, but its relative contribution to the risk of recurrence is not well-defined. Co-existing BRAF V600E and TERT mutations act synergically to increase the risk of recurrence[25,26].…”

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confidence: 99%

Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

et al. 2019

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“…Additionally, mutation in the TERT promoter has shown to have prognostic value across a range of tumors [4,33,37,[41][42][43][44][45]. Mutations in this promoter region maintain telomere length and tumor cell survival which plays a crucial role in cancer development [46].…”

Section: Discussionmentioning

confidence: 99%

The interaction between TERT promoter mutation and MGMT promoter methylation on overall survival of glioma patients: a meta-analysis

Vuong

Nguyen

Ngo

et al. 2020

Preprint

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Background There are controversial results concerning the prognostic implication of TERT promoter mutation in glioma patients concerning MGMT status. In this meta-analysis, we investigated whether there are any interactions of these two genetic markers on the overall survival (OS) of glioma patients. Methods Electronic databases including PubMed and Web of Science were searched for relevant studies. Hazard ratio (HR) and its 95% confidence interval (CI) for OS adjusted for selected covariates were calculated from the individual patient data (IPD), Kaplan-Meier curve (KMC), or directly obtained from the included studies. Results A total of nine studies comprising 2819 glioma patients were included for meta-analysis. Our results showed that TERT promoter mutation was associated with a superior outcome in MGMT-methylated gliomas (HR = 0.73; 95% CI = 0.55-0.98; p-value = 0.04), whereas this mutation was associated with poorer survival in gliomas without MGMT methylation (HR = 1.86; 95% CI = 1.54-2.26; p-value < 0.001). TERT-mutated glioblastoma (GBM) patients with MGMT methylation benefited from temozolomide (TMZ) treatment (HR = 0.33; 95% CI = 0.23-0.47; p-value < 0.001). MGMT methylation was not related with any improvement in OS in TERT-wild type GBMs (HR = 0.80; 95% CI = 0.56-1.15; p-value = 0.23).ConclusionsThe prognostic value of TERT promoter mutation may be modulated by MGMT methylation status. Not all MGMT-methylated GBM patients may benefit from TMZ; it is possible that only TERT-mutated GBM with MGMT methylation, in particular, may respond.

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Prognostic implication of BRAF and TERT promoter mutation combination in papillary thyroid carcinoma—A meta‐analysis

Abstract: The risk stratification of PTC based on these four genotypes can help improve the clinical management of PTCs by identifying the group of PTCs with the highest aggressiveness.

Cited by 117 publications

References 28 publications

The Solo Play of TERT Promoter Mutations

The Solo Play of TERT Promoter Mutations

Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

The interaction between TERT promoter mutation and MGMT promoter methylation on overall survival of glioma patients: a meta-analysis

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