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Donghyun D. Lee, … , Pedro Castelo-Branco, Uri Tabori
Published October 25, 2018
Citation Information: J Clin Invest. 2019;129(1):223-229. https://doi.org/10.1172/JCI121303.
Citation Information: J Clin Invest. 2019;129(1):223-229. https://doi.org/10.1172/JCI121303.
Abstract
Replicative immortality is a hallmark of cancer cells governed by telomere maintenance. Approximately 90% of human cancers maintain their telomeres by activating telomerase, driven by the transcriptional upregulation of telomerase reverse transcriptase (TERT). Although TERT promoter mutations (TPMs) are a major cancer-associated genetic mechanism of TERT upregulation, many cancers exhibit TERT upregulation without TPMs. In this study, we describe the TERT hypermethylated oncological region (THOR), a 433-bp genomic region encompassing 52 CpG sites located immediately upstream of the TERT core promoter, as a cancer-associated epigenetic mechanism of TERT upregulation. Unmethylated THOR repressed TERT promoter activity regardless of TPM status, and hypermethylation of THOR counteracted this repressive function. THOR methylation analysis in 1,352 human tumors revealed frequent (>45%) cancer-associated DNA hypermethylation in 9 of 11 (82%) tumor types screened. Additionally, THOR hypermethylation, either independently or along with TPMs, accounted for how approximately 90% of human cancers can aberrantly activate telomerase. Thus, we propose that THOR hypermethylation is a prevalent telomerase-activating mechanism in cancer that can act independently of or in conjunction with TPMs, further supporting the utility of THOR hypermethylation as a prognostic biomarker.
Authors
Donghyun D. Lee, Ricardo Leão, Martin Komosa, Marco Gallo, Cindy H. Zhang, Tatiana Lipman, Marc Remke, Abolfazl Heidari, Nuno Miguel Nunes, Joana D. Apolónio, Aryeh J. Price, Ramon Andrade De Mello, João S. Dias, David Huntsman, Thomas Hermanns, Peter J. Wild, Robert Vanner, Gelareh Zadeh, Jason Karamchandani, Sunit Das, Michael D. Taylor, Cynthia E. Hawkins, Jonathan D. Wasserman, Arnaldo Figueiredo, Robert J. Hamilton, Mark D. Minden, Khalida Wani, Bill Diplas, Hai Yan, Kenneth Aldape, Mohammad R. Akbari, Arnavaz Danesh, Trevor J. Pugh, Peter B. Dirks, Pedro Castelo-Branco, Uri Tabori
Total citations by year
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BM Nogueira, CB Machado, RC Montenegro, ME Moraes, CA Moreira-Nunes |
In vivo (Athens, Greece) | 2020 |
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Poly(U) binding splicing factor 60 promotes renal cell carcinoma growth by transcriptionally upregulating telomerase reverse transcriptase
Q Long, Y Hua, L He, C Zhang, S Sui, Y Li, H Qiu, T Tian, X An, G Luo, Y Yan, A Zhao, D Shi, F Xie, M Chen, F Zheng, W Deng |
International journal of biological sciences | 2020 |
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Long Telomeres and Cancer Risk: the Price of Cellular Immortality
Emily McNally, Paz J Luncsford, Mary Armanios |
Journal of Clinical Investigation | 2019 |
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Telomere Maintenance in Pediatric Cancer
Ackermann, Fischer |
International journal of molecular sciences | 2019 |
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Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players
X Yuan, C Larsson, D Xu |
Oncogene | 2019 |
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Telomerase Reverse Transcriptase (TERT) in Action: Cross-Talking with Epigenetics
X Yuan, D Xu |
International journal of molecular sciences | 2019 |
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Analysis of the Clinical Relevance of Histological Classification of Benign Epithelial Salivary Gland Tumours
H Hellquist, A Paiva-Correia, VV Poorten, M Quer, JC Hernandez-Prera, S Andreasen, P Zbären, A Skalova, A Rinaldo, A Ferlito |
Advances in Therapy | 2019 |
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Association between methylation in nasal epithelial TSLP gene and chronic rhinosinusitis with nasal polyps
J Li, J Jiao, Y Gao, Y Zhang, L Zhang |
Allergy Asthma & Clinical Immunology | 2019 |
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Validation of a Novel, Sensitive, and Specific Urine-Based Test for Recurrence Surveillance of Patients With Non-Muscle-Invasive Bladder Cancer in a Comprehensive Multicenter Study
R Batista, J Vinagre, H Prazeres, C Sampaio, P Peralta, P Conceição, A Sismeiro, R Leão, A Gomes, F Furriel, C Oliveira, JN Torres, P Eufrásio, P Azinhais, F Almeida, ER Gonzalez, B Bidovanets, T Ecke, P Stinjs, ÁS Pascual, R Abdelmalek, A Villafruela, P Beardo-Villar, N Fidalgo, H Öztürk, C Gonzalez-Enguita, J Monzo, T Lopes, M Álvarez-Maestro, PP Servan, SM Cruz, MP Perez, V Máximo, P Soares |
Frontiers in Genetics | 2019 |
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Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd |
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology | 2009 |
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