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J Clin Invest. 2019 Jan 2;129(1):223-229. doi: 10.1172/JCI121303. Epub 2018 Dec 3.

DNA hypermethylation within TERT promoter upregulates TERT expression in cancer.

Author information

1
Program in Genetics and Genome Biology, and.
2
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
3
Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
4
Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
5
Departments of Physiology and Pharmacology, Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
6
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
7
Department of Biomedical Sciences and Medicine, and.
8
Centro Hospitalar Universitário do Algarve, Faro, Portugal.
9
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
10
Department of Urology, University Hospital Zürich, and.
11
Institute of Pathology and Molecular Pathology, University Hospital Zürich, University of Zürich, Zürich, Switzerland.
12
Division of Neurosurgery, University of Toronto, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
13
Department of Pathology, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
14
Division of Endocrinology, The Hospital for Sick Children, Toronto, Ontario, Canada.
15
Division of Urology, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
16
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
17
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
18
Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA.
19
Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada.
20
Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.

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.

KEYWORDS:

Cancer; Epigenetics; Oncology; Telomeres

PMID:
30358567
PMCID:
PMC6307937
DOI:
10.1172/JCI121303
[Indexed for MEDLINE]
Free PMC Article

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