Cancer-associated TERT promoter mutations abrogate telomerase silencing

Chiba, Kunitoshi; Johnson, Joshua Z; Vogan, Jacob M.; Wagner, Tina; Boyle, John M; Hockemeyer, Dirk

doi:10.7554/elife.07918

Cited by 225 publications

(242 citation statements)

References 52 publications

(72 reference statements)

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“…Mechanistic studies have, however, shown that the embryonic stem cells engineered to carry the TERT promoter mutations, upon differentiation into somatic cells, failed to silence TERT expression leading to active telomerase and long telomeres. 42 Telomerase reactivation in tumors with telomere dysfunction has been shown to lead to malignant progression of prostate cancer in a mouse model. 43 Conversely, suppression of telomerase activity had shown to significantly reduce tumor invasion and metastatic potential in a melanoma mouse model.…”

Section: Cancer Genetics and Epigeneticsmentioning

confidence: 99%

TERT promoter mutations in melanoma survival

Nagore

Heidenreich

Rachakonda

et al. 2016

Intl Journal of Cancer

102

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Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at-risk primary melanoma patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression-free and melanoma-specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease-free and melanoma-specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease-free survival was 2.3 (95% CI 1.2-4.4) and for melanoma-specific survival 5.8 (95% CI 1.9-18.3). The effect of the mutations on melanoma-specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4-15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1-0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter.Cutaneous melanoma represents one of the most aggressive skin cancers with its propensity to metastasize and intrinsic resistance to treatment. 1 A majority of melanomas remain localized; however, in a proportion of patients, the tumors metastasize to local and distant organs with dismal outcomes.The refractoriness to treatment of patients with metastasized melanoma has been the main cause of the deaths associated with the disease. 2 Despite increased possibilities, with range of treatments including targeted and immunotherapies, of eliciting stable responses in patients with metastatic melanoma, the long-term prospectus in terms of treatment response is confined to disease management. 3 The identification of patients at risk of developing advanced disease at an early stage through use of somatic mutations as molecular biomarkers remains a valid medical issue.The melanoma genome is characterized by one of the highest prevalence of somatic mutations, and the mutational pattern depicts characteristic ultraviolet signature. 4 Besides recurrent mutations in TERT promoter, BRAF/NRAS, CDKN2A, NF1, PTEN and others genes, various sequencing initiatives have identified mutations in a number of other genes including GRIN2A, RAC1, BCL2L12, STK19, FBXW7 and RPS27. [5][6][7][8][9][10][11][12][13][14] The mutations in the promoter of TERT gene, mainly at 2124 (...

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Section: Cancer Genetics and Epigeneticsmentioning

confidence: 99%

TERT promoter mutations in melanoma survival

Nagore

Heidenreich

Rachakonda

et al. 2016

Intl Journal of Cancer

102

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“…This effect was independent from BRAF and RAS status. Nevertheless, it cannot be excluded that TERT promoter alterations may also act as early genetic hit, as mutations have been detected across all stages and grades in most cancers (Chiba et al 2015). Indeed, mutations are detected alone in a small but non-negligible portion of DTC, even if prognostic effect is lost or extremely mild in this case, as already discussed in the previous paragraph.…”

Section: Co-occurrence Of Driver Mutationsmentioning

confidence: 67%

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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“…The results of the present study did not reveal a significant association between TERT promoter mutation and relative telomere length in the GBM samples. Previous studies demonstrated that the association between telomere length and TERT expression is complex and may be regulated by a number of other factors, including the activities of signaling pathways and alterations of genes (4,28,29). Previous studies have demonstrated that TERT promoter is the most common type of mutation in GBMs, suggesting that it may be an early event in GBM carcinogenesis (2,4,5,(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

Preclinical and clinical implications of TERT promoter mutation in glioblastoma multiforme

et al. 2017

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Abstract. The promoter region of the telomerase reverse transcriptase gene (TERT) is mutated in a subpopulation of patients with glioblastoma multiforme (GBM). In the present study, preclinical and clinical implications of the mutation were analyzed in 25 GBMs to evaluate its utility as a therapeutic target. Associations between the TERT promoter mutation and a number of preclinical/clinical characteristics were analyzed. Notably, the TERT promoter mutation was identified in 92.3% of GBMs where dissociated cells revealed in vitro sphere formation capacity; while the TERT promoter mutation was identified in 33.3% of GBMs without in vitro sphere formation capacity (P= 0.004). In addition, this significantly increased mutation rate was observed in GBMs with in vivo tumorigenic potential (80% vs. 0%; P= 0.004). Furthermore, patients with GBM exhibiting the TERT promoter mutation demonstrated significantly decreased overall survival rate compared with patients lacking this mutation (81.7 vs. 152.6 weeks; P=0.026). The results of the present study indicated that the TERT promoter mutation is associated with the self-renewal capacity of GBM cells and clinical aggressiveness of GBMs, which may be translated to a targeting therapy against TERT to inhibit the self-renewal of GBM cells.

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Cancer-associated TERT promoter mutations abrogate telomerase silencing

Cited by 225 publications

References 52 publications

TERT promoter mutations in melanoma survival

TERT promoter mutations in melanoma survival

Application of molecular biology of differentiated thyroid cancer for clinical prognostication

Preclinical and clinical implications of TERT promoter mutation in glioblastoma multiforme

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