Journal Article

DNA hypermethylation within TERT promoter upregulates TERT expression in cancer

Dirks, Peter B., Hamilton, Robert J., Yan, Hai, Karamchandani, Jason, Wasserman, Jonathan D., Tabori, Uri, Danesh, Arnavaz, Castelo-Branco, Pedro, Aldape, Kenneth, Lee, Donghyun D., Wild, Peter J., Huntsman, David, Price, Aryeh J., Pugh, Trevor J., Heidari, Abolfazl, Minden, Mark D., Zhang, Cindy H., Figueiredo, Arnaldo, Leão, Ricardo, Wani, Khalida, Diplas, Bill, Dias, João S., Gallo, Marco, Remke, Marc, Apolónio, Joana D., Zadeh, Gelareh, Das, Sunit, Lipman, Tatiana, Hermanns, Thomas, Vanner, Robert, Komosa, Martin, Hawkins, Cynthia E., Taylor, Michael D., Akbari, Mohammad R., Nunes, Nuno Miguel, De Mello, Ramon Andrade

2019

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Biomedical research / Brain cancer / Cancer / Cell Line, Tumor / Concise Communication / CpG Islands / Deoxyribonucleic acid / DNA / DNA Methylation / DNA, Neoplasm - genetics / DNA, Neoplasm - metabolism / Epigenetics / Gene Expression Regulation, Enzymologic / Gene Expression Regulation, Neoplastic / Gene mutation / Genes / Genetic aspects / Genetic testing / Humans / Methylation / Mutation / Neoplasm Proteins - biosynthesis / Neoplasm Proteins - genetics / Promoter Regions, Genetic / Prostate cancer / RNA-directed DNA polymerase / Studies / Telomerase / Telomerase - biosynthesis / Telomerase - genetics / Telomerase reverse transcriptase / Telomeres / Thyroid gland / Transcription / Tumors