DNA hypermethylation within TERT promoter upregulates TERT expression in cancer.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Lee, DD; Leão, R; Komosa, M; Gallo, M; Zhang, CH; Lipman, T; Remke, M; Heidari, A; Nunes, NM; Apolónio, JD; Price, AJ; De Mello, RA; Dias, JS; Huntsman, D; Hermanns, T; Wild, PJ; Vanner, R; Zadeh, G; Karamchandani, J; Das, S; Taylor, MD; Hawkins, CE; Wasserman, JD; Figueiredo, A; Hamilton, RJ; Minden, MD; Wani, K; Diplas, B; Yan, H; Aldape, K; Akbari, MR; Danesh, A; Pugh, TJ; Dirks, PB; Castelo-Branco, P; Tabori, U

Published Date

  • January 2, 2019

Published In

Volume / Issue

  • 129 / 1

Start / End Page

  • 223 - 229

PubMed ID

  • 30358567

Pubmed Central ID

  • 30358567

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI121303

Language

  • eng

Conference Location

  • United States