Pervasive promoter hypermethylation of silenced TERT alleles in human cancers

David Esopi, Mindy Kim Graham, Jacqueline A. Brosnan-Cashman, Jennifer Meyers, Ajay Vaghasia, Anuj Gupta, Balasubramanian Kumar, Michael C. Haffner, Christopher M. Heaphy, Angelo M. De Marzo, Alan K. Meeker, William G. Nelson, Sarah J. Wheelan, Srinivasan Yegnasubramanian

Research output: Contribution to journalArticlepeer-review

Abstract

Background: In cancers, maintenance of telomeres often occurs through activation of the catalytic subunit of telomerase, encoded by TERT. Yet, most cancers show only modest levels of TERT gene expression, even in the context of activating hotspot promoter mutations (C228T and C250T). The role of epigenetic mechanisms, including DNA methylation, in regulating TERT gene expression in cancer cells is as yet not fully understood. Methods: Here, we have carried out the most comprehensive characterization to date of TERT promoter methylation using ultra-deep bisulfite sequencing spanning the CpG island surrounding the core TERT promoter in 96 different human cell lines, including primary, immortalized and cancer cell types, as well as in control and reference samples. Results: In general, we observed that immortalized and cancer cell lines were hypermethylated in a region upstream of the recurrent C228T and C250T TERT promoter mutations, while non-malignant primary cells were comparatively hypomethylated in this region. However, at the allele-level, we generally found that hypermethylation of promoter sequences in cancer cells is associated with repressed expression, and the remaining unmethylated alleles marked with open chromatin are largely responsible for the observed TERT expression in cancer cells. Conclusions: Our findings suggest that hypermethylation of the TERT promoter alleles signals transcriptional repression of those alleles, leading to attenuation of TERT activation in cancer cells. This type of fine tuning of TERT expression may account for the modest activation of TERT expression in most cancers.

Original languageEnglish (US)
Pages (from-to)847-861
Number of pages15
JournalCellular Oncology
Volume43
Issue number5
DOIs
StatePublished - Oct 1 2020

Keywords

  • Cancer
  • DNA methylation
  • Epigenetics
  • High-throughput sequencing
  • TERT promoter mutation
  • Telomerase regulation
  • Telomeres and telomerase

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

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