DNA hypermethylation within TERT promoter upregulates TERT expression in cancer
Donghyun D. Lee, … , Pedro Castelo-Branco, Uri Tabori
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.
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Concise Communication Oncology

DNA hypermethylation within TERT promoter upregulates TERT expression in cancer

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

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Figure 4

Coexistence and interplay of TPM and THOR hypermethylation in human cancers.

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Coexistence and interplay of TPM and THOR hypermethylation in human canc...
For the data shown, each experiment was performed in triplicate. (A) Normalized fold changes in TERT promoter activity are shown for the specified luciferase constructs, with the presence and absence of THOR and/or C228T TPM, in the glioblastoma cell line LN229 and the medulloblastoma cell lines ONS76 and UW228. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired t test. (B) TERT expression (mean ± SD, black bars and dots, y axis) and average THOR methylation levels (red dots, y axis) are shown in human primary (1°) and cancer cell lines. TERT regulation–associated characteristics for all cell lines are shown below the graph. (C) Pie charts display the frequencies of TPMs and the THOR hypermethylation signature in TPM-common tumors (gliomas and melanomas) and TPM-independent tumors (prostate, lung, colon, and breast). (D) TERT expression (mean ± SD, black bars and dots, y axis) and THOR methylation levels (red dots, y axis) are shown in a subset of adult gliomas (n = 21). TERT regulation–associated characteristics for these samples are shown below the graph.