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 2

THOR hypermethylation is prevalent in human cancers.

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THOR hypermethylation is prevalent in human cancers. (A) Average DNA CpG...
(A) Average DNA CpG methylation of the TERT promoter in normal cell lines and tissues (n = 43, blue) and tumor samples (n = 87, red). (B) Methylation heatmap generated from unsupervised clustering shows the methylation percentage of each CpG site within THOR for normal cell lines and tissues (n = 43) and tumor samples (n = 87). Gray color indicates unavailability of data. (C) Box-and-whisker plot shows the median and distribution of the average THOR methylation levels in normal control samples (n = 80, blue) and samples from various tumor tissue types (n = 1,352; red). *P < 0.05, by Sidak’s multiple comparisons test. (D) Difference in average THOR methylation levels between each pair of normal tumor samples (n = 99; left plot) and distribution of differences in THOR methylation (right plot; median and IQR). ****P < 0.0001, by paired t test. (E) Pie charts display the frequencies of the THOR hypermethylation signature across various tumor types.