First published April 1, 2019 - More info
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.
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
Original citation: J Clin Invest. 2019;129(1):223–229. https://doi.org/10.1172/JCI121303
Citation for this corrigendum: J Clin Invest. 2019;129(4):1801. https://doi.org/10.1172/JCI128527
Of the 1352 samples in the cohort, which were provided by multiple collaborators, four samples of breast tissue for which DNA was analyzed were a part of another study. Since these samples did not go through the same rigorous screening process, including pathology review and extraction of DNA from paraffin tissues, that was applied to all other samples, the authors are less confident in their exact identity and have decided to retract them from the study. This does not change the message of the paper, but results in changes in and in one pie chart in Figure 2E, that for breast cancer. The corrected figure parts are below. In addition, the supplemental material containing sample information has been updated online.
The authors regret the error.
See the related article at DNA hypermethylation within TERT promoter upregulates TERT expression in cancer.