Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation

Li, Yinghui; Zhou, Qi; Sun, Wenjie; Chandrasekharan, Prashant; Cheng, Hui; Ying, Zhe; Lakshmanan, Manikandan; Raju, Anandhkumar; Tenen, Daniel G.; Cheng, Shi Yuan; Chuang, Kai‐Hsiang; Li, Jun; Prabhakar, Shyam; Li, Mengfeng; Tergaonkar, Vinay

doi:10.1038/ncb3240

Cited by 192 publications

(211 citation statements)

References 69 publications

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“…We were unable to test whether or not the observed differences in the extent of MGMT methylation actually reflect differences in tumor purity because of the required quantile normalization between the C228 and C250 qAS-PCR assays. Similarly, several studies have shown differences in TERT mRNA expression levels between the two hotspot mutations with higher expression in C250T-mutated GBM samples (23,40). We observed the same trend in our data, but we instead propose attributing this finding to collinearity with tumor purity.…”

Section: Discussioncontrasting

confidence: 50%

“…This is perhaps reasonable as both hotspot mutations are known to generate an identical Ets/TCF transcription factorbinding motif (37)(38)(39). Very recently, however, functional differences between the C228T and C250T mutations with respect to NF-kB pathway activation has been reported (40). Profound biological differences, for example, in tumor purity, between tumors carrying the C228T versus the C250T point mutation are thus likely.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

Heuling

Knab

Radke

et al. 2017

Molecular Cancer Research

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Promoter methylation status of O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, is a critical biomarker in glioblastoma (GBM), as treatment decisions and clinical trial inclusion rely on its accurate assessment. However, interpretation of results is complicated by poor interassay reproducibility as well as a weak correlation between methylation status and expression levels of MGMT. This study systematically investigates the influence of tumor purity on tissue subjected to MGMT analysis. A quantitative, allele-specific realtime PCR (qAS-PCR) assay was developed to determine genotype and mutant allele frequency of telomerase promoter (pTERT) mutations as a direct measure of tumor purity. We studied tumor purity, pTERT mutation by Sanger sequencing, MGMT methylation by pyrosequencing, IDH1 mutation status, and clinical parameters in a cohort of high-grade gliomas (n ¼ 97). The qAS-PCR reliably predicted pTERT genotype and tumor purity compared with independent methods. Tumor purity positively and significantly correlated with the extent of methylation in MGMT methylated GBMs. Extent of MGMT methylation differed significantly with respect to pTERT mutation hotspot (C228T vs. C250T). Interestingly, frontal lobe tumors showed greater tumor purity than those in other locations. Above all, tumor purity was identified as an independent prognostic factor in GBM. In conclusion, we determined mutual associations of tumor purity with MGMT methylation and pTERT mutations and found that the extent of MGMT methylation reflects tumor purity. In turn, tumor purity is prognostic in IDH1 wild-type GBM.Implications: Tumor purity is an independent prognostic marker in glioblastoma and is associated with the extent of MGMT methylation. Mol Cancer Res; 15(5); 532-40. Ó2017 AACR.

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Section: Discussioncontrasting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

Heuling

Knab

Radke

et al. 2017

Molecular Cancer Research

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“…40 The 2146C>T mutation in the TERT promoter, on the other hand, has been shown to be driven by noncanonical NF-kB signaling. 41 Incidentally, in melanoma both 2124C>T and 2146C>T mutations occur at almost similar frequencies; in all other malignancies the former mutation is overwhelmingly predominant. 39 Telomerase activity in human tissues is restricted due to transcriptional silencing of TERT following differentiation.…”

Section: Cancer Genetics and Epigeneticsmentioning

confidence: 99%

TERT promoter mutations in melanoma survival

Nagore

Heidenreich

Rachakonda

et al. 2016

Intl Journal of Cancer

107

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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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“…Another study in glioblastoma, reported that although the −124C > T and −146C > T mutations create similar binding motif sequences, they are distinct functionally (Li et al 2015b). The −146C > T creates a specific binding site for p52 being driven by non-canonical NF-κB signalling pathway (Li et al 2015b).…”

Section: Functional Effects Of Tert Promoter Mutations In Tumours Andmentioning

confidence: 99%

“…The −146C > T creates a specific binding site for p52 being driven by non-canonical NF-κB signalling pathway (Li et al 2015b). Li and coworkers also elucidate that the binding of ETS alone is ineffective in the activation of TERT transcription in the −146C > T mutation (Li et al 2015b).…”

Section: Functional Effects Of Tert Promoter Mutations In Tumours Andmentioning

confidence: 99%

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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Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation

Cited by 192 publications

References 69 publications

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

TERT promoter mutations in melanoma survival

TERT biology and function in cancer: beyond immortalisation

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