Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients

Song, Young Shin; Lim, Joo Hyun; Choi, Hyo Geun; Won, Jae Kyung; Moon, Jae Hoon; Cho, Sun Wook; Lee, Kyu Eun; Park, Young Joo; Yi, Ka Hee; Park, Do Joon; Seo, Jeong Sun

doi:10.1002/cncr.29934

Cited by 155 publications

(172 citation statements)

References 26 publications

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“…Some groups report that co-occurrence of TERT promoter and BRAF mutations are associated with worse prognosis factors in thyroid cancer (Allory et al 2014, 2016a, Song et al 2016, whereas other authors have not found this association in other series (Melo et al 2014, George et al 2015, Nasirden et al 2016.…”

Section: Tert Promoter Mutations In Thyroid Cancermentioning

confidence: 94%

TERT biology and function in cancer: beyond immortalisation

Pestana

Vinagre

Sobrinho-Simões

et al. 2017

Journal of Molecular Endocrinology

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Evasion of replicative senescence and proliferation without restriction, sometimes designated as immortalisation, is one of the hallmarks of cancer that may be attained through reactivation of telomerase in somatic cells. In contrast to most normal cells in which there is lack of telomerase activity, upregulation of TERT transcription/activity is detected in 80-90% of malignant tumours. In several types of cancer, there is a relationship between the presence of TERT promoter mutations, TERT mRNA expression and clinicopathological features, but the biological bridge between the occurrence of TERT promoter mutations and the aggressive/invasive features displayed by the tumours remains unidentified. We and others have associated the presence of TERT promoter mutations with metastisation/survival in several types of cancer. In follicular cell-derived thyroid cancer, such mutations are associated with worse prognostic features (age of patients, tumour size and tumour stage) as well as with distant metastases, worse response to treatment and poorer survival. In this review, we analyse the data reported in several studies that imply TERT transcription reactivation/activity with cell proliferation, tumour invasion and metastisation. A particular attention is given to the putative connections between TERT transcriptional reactivation and signalling pathways frequently altered in cancer, such as c-MYC, NF-κB and B-Catenin.

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Section: Tert Promoter Mutations In Thyroid Cancermentioning

confidence: 94%

TERT biology and function in cancer: beyond immortalisation

Pestana

Vinagre

Sobrinho-Simões

et al. 2017

Journal of Molecular Endocrinology

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“…Gland Surg 2016;5(5):495-505 gs.amegroups.com aggressive clinical course. It is believed that more accurate tumor prognostication is possible due to a genetic analysis (55)(56)(57)(58).…”

Section: Ata Modified Initial Risk Stratification Systemmentioning

confidence: 99%

BRAF V600E mutation in prognostication of papillary thyroid cancer (PTC) recurrence

Czarniecka¹,

Oczko-Wojciechowska²,

Barczyński³

2016

Gland Surg.

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Papillary thyroid cancer (PTC) offers excellent prognosis, however relapse risk or persistent disease is related to ~30%. Currently, attention is paid to the possibility of patient group selection of different risk of unfavorable outcome to match a particular therapeutic approach. Therefore, interest in new prognostic and predictive markers known preoperatively is observed. BRAF V600E mutation is such a marker. Many studies analyzing the prevalence of the mutation and its relationship with other clinicopathological risk factors were reported but with controversial conclusions. The prognostic significance of BRAF mutation was confirmed by some single centre studies, a few meta-analyses and a large multicenter retrospective international study. They confirmed a correlation between the mutation and the risk of recurrence. The strongest argument against using BRAF mutation as an independent prognostic and predictive factor in PTC is its high prevalence (30-80%). At present it seems that BRAF mutation is one of the factors influencing the prognosis and it should be analyzed in correlation with other prognostic factors.The most recent ATA recommendations do not indicate a routine application of BRAF status for initial risk stratification in differentiated thyroid cancer due to a lack of evident confirmation of a direct influence of mutation on the increase in relapse risk. However, ATA demonstrates the continuous risk scale for the relapse risk assessment, considering BRAF and/or TERT status. At present, researchers are working on determining the role of BRAF mutation in patients from a low-risk group and its correlations with others molecular events. Currently, BRAF mutation cannot be used as a single, independent predictive factor. However, its usefulness in the context of other molecular and clinico-pathological risk factors cannot be excluded. They may be used to make modern prognostic scales of relapse risk and be applied to individualized diagnostic and therapeutic strategy for PTC patients.

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“…This body of evidence led a wide part of literature dealing with DTC to categorise prognostic effect of TERT promoter mutations as dramatic, even overcoming prognostic performance of the BRAF V600E oncogene, which was historically considered as the best molecular prognosticator (as discussed previously). Nevertheless, this was misleading as recently demonstrated by a series of studies performing simultaneous analysis of TERT promoter and BRAF (Xing et al 2014a,b, Liu et al 2014b, Song et al 2016. Indeed, all these papers consistently showed that prognostic effect related to alterations of TERT promoter disappeared or strikingly decreased when mutations occurred separately (Fig.…”

Section: Emerging Molecular Prognosticators: Tert Promoter and Tp53 Mmentioning

confidence: 91%

“…They found that the 2 molecular abnormalities were synergic in increasing the risk of persistent disease, but failed to demonstrate similar interaction for the risk of tumour recurrence. More recently, the aforementioned study by Song (Song et al 2016) showed a synergistic effect between RAS and TERT promoter mutations in worsening clinico-pathological features and outcome of DTC patients, including both tumour recurrence and diseaserelated mortality. Although further studies are needed to assess the actual interplay with RAS status, the presence of TERT promoter mutations may allow the identification of a subgroup of aggressive tumours within both BRAFand RAS-mutated DTC, which represent the main clinicomolecular types (Agrawal et al 2014).…”

Section: Co-occurrence Of Driver Mutationsmentioning

confidence: 99%

“…It is conceivable that BRAF and RAS alterations may act as early mutational events, whereas TERT promoter mutations may represent a late genetic hit, increasing the proliferative potential of cancer cells and therefore stimulating disease progression. The hypothesis of the late occurrence of TERT promoter mutations as a key point for tumour progression in DTC is sustained by a specific finding from the study by Song (Song et al 2016), as authors demonstrated that mutations significantly worsened the prognosis of patients with advanced disease. This effect was independent from BRAF and RAS status.…”

Section: Co-occurrence Of Driver Mutationsmentioning

confidence: 99%

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Application of molecular biology of differentiated thyroid cancer for clinical prognostication

Marotta¹,

Sciammarella²,

Colao³

et al. 2016

Endocrine-Related Cancer

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Although cancer outcome results from the interplay between genetics and environment, researchers are making a great effort for applying molecular biology in the prognostication of differentiated thyroid cancer (DTC). Nevertheless, role of molecular characterisation in the prognostic setting of DTC is still nebulous. Among the most common and well-characterised genetic alterations related to DTC, including mutations of BRAF and RAS and RET rearrangements, BRAF V600E is the only mutation showing unequivocal association with clinical outcome. Unfortunately, its accuracy is strongly limited by low specificity. Recently, the introduction of next-generation sequencing techniques led to the identification of TERT promoter and TP53 mutations in DTC. These genetic abnormalities may identify a small subgroup of tumours with highly aggressive behaviour, thus improving specificity of molecular prognostication. Although knowledge of prognostic significance of TP53 mutations is still anecdotal, mutations of the TERT promoter have showed clear association with clinical outcome. Nevertheless, this genetic marker needs to be analysed according to a multigenetic model, as its prognostic effect becomes negligible when present in isolation. Given that any genetic alteration has demonstrated, taken alone, enough specificity, the co-occurrence of driving mutations is emerging as an independent genetic signature of aggressiveness, with possible future application in clinical practice. DTC prognostication may be empowered in the near future by non-tissue molecular prognosticators, including circulating BRAF V600E and miRNAs. Although promising, use of these markers needs to be refined by the technical sight, and the actual prognostic value is still yet to be validated. 23:11Review V Marotta et al. Molecular prognosis in thyroid cancer

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Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients

Cited by 155 publications

References 26 publications

TERT biology and function in cancer: beyond immortalisation

TERT biology and function in cancer: beyond immortalisation

BRAF V600E mutation in prognostication of papillary thyroid cancer (PTC) recurrence

Application of molecular biology of differentiated thyroid cancer for clinical prognostication

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