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Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer
Donghyun D. Lee, … , Nuno Miguel Nunes, Uri Tabori
Donghyun D. Lee, … , Nuno Miguel Nunes, Uri Tabori
Published November 1, 2021
Citation Information: J Clin Invest. 2021;131(21):e146915. https://doi.org/10.1172/JCI146915.
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Research Article Genetics Oncology Article has an altmetric score of 12

Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer

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Abstract

Aberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allele-specific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer.

Authors

Donghyun D. Lee, Martin Komosa, Sumedha Sudhaman, Ricardo Leão, Cindy H. Zhang, Joana D. Apolonio, Thomas Hermanns, Peter J. Wild, Helmut Klocker, Farshad Nassiri, Gelareh Zadeh, Bill H. Diplas, Hai Yan, Steven Gallinger, Trevor J. Pugh, Vijay Ramaswamy, Michael D. Taylor, Pedro Castelo-Branco, Nuno Miguel Nunes, Uri Tabori

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Figure 1

Prevalence of THOR-DAM in human cancer.

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Prevalence of THOR-DAM in human cancer.
(A) Schematic of the TERT promot...
(A) Schematic of the TERT promoter. Black lollipops represent CpG sites. Red bar indicates the region of DAM assessment within THOR. (B) Bean plot displaying the distribution of the allelic methylation difference in each tumor type. Each white line shows a methylation difference between the low- and high-methylated alleles in a sample, with the mean difference for each tumor type shown in a black line. Turquoise bars and pink bars indicate the tumor types with low and high prevalence of TPMs based on the previous literature (31). (C) Difference in methylation levels of the alleles separated with pSNP (A vs. G SNPs, rs2853669) within each tumor sample. Each pair of blue and red dots represents a tumor sample. Blue dots and red dots represent methylation levels of lower and higher methylated alleles, respectively. Orange dotted lines indicate the samples that are THOR-DAM. (D) Pie graphs showing prevalence of DAM and THOR hypermethylation in each tumor types (red = presence of attribute, blue = absence of attribute).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 2 patents
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