1. Duplo papel de hipermetilação de DNA específica de alelo dentro do TERT no câncer
- Author
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Pedro Castelo-Branco, Sumedha Sudhaman, Hai Yan, Martin Komosa, Ricardo Leão, Bill H. Diplas, Uri Tabori, Cindy Zhang, Vijay Ramaswamy, Thomas Hermanns, Gelareh Zadeh, Farshad Nassiri, Donghyun Lee, Nuno Miguel Nunes, Michael D. Taylor, Trevor J. Pugh, Steven Gallinger, Joana D Apolonio, Peter J. Wild, Helmut Klocker, University of Zurich, and Tabori, Uri
- Subjects
Telomerase ,Metilação ,610 Medicine & health ,2700 General Medicine ,Biology ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,medicine ,Humans ,Epigenetics ,Allele ,Promoter Regions, Genetic ,030304 developmental biology ,0303 health sciences ,Mutações do promotor ,Cancer ,Promoter ,Expressão ,General Medicine ,Methylation ,DNA, Neoplasm ,DNA Methylation ,medicine.disease ,3. Good health ,Telomere ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,10062 Urological Clinic ,Telômeros ,030220 oncology & carcinogenesis ,DNA methylation ,Cancer research ,Research Article - 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 allelespecific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer. info:eu-repo/semantics/publishedVersion
- Published
- 2021