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

2021-11-01Journal article Open access
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dc.contributor.authorLee, Donghyun D.
dc.contributor.authorKomosa, Martin
dc.contributor.authorSudhaman, Sumedha
dc.contributor.authorLeão, Ricardo
dc.contributor.authorZhang, Cindy H.
dc.contributor.authorApolonio, Joana D.
dc.contributor.authorHermanns, Thomas
dc.contributor.authorWild, Peter J.
dc.contributor.authorKlocker, Helmut
dc.contributor.authorNassiri, Farshad
dc.contributor.authorZadeh, Gelareh
dc.contributor.authorDiplas, Bill H.
dc.contributor.authorYan, Hai
dc.contributor.authorGallinger, Steven
dc.contributor.authorPugh, Trevor J.
dc.contributor.authorRamaswamy, Vijay
dc.contributor.authorTaylor, Michael D.
dc.contributor.authorCastelo-Branco, Pedro
dc.contributor.authorNunes, Nuno Miguel
dc.contributor.authorTabori, Uri
dc.date.accessioned2021-11-23T16:23:07Z
dc.date.available2021-11-23T16:23:07Z
dc.date.issued2021-11-01
dc.description.abstractAberrant 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1172/JCI146915pt_PT
dc.identifier.eissn1558-8238
dc.identifier.urihttp://hdl.handle.net/10400.1/17348
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Soc Clinical Investigation Incpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectMutações do promotorpt_PT
dc.subjectMetilaçãopt_PT
dc.subjectExpressãopt_PT
dc.subjectTelômerospt_PT
dc.titleDual role of allele-specific DNA hypermethylation within the TERT promoter in cancerpt_PT
dc.title.alternativeDuplo papel de hipermetilação de DNA específica de alelo dentro do TERT no câncerpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue21pt_PT
oaire.citation.titleJournal of Clinical Investigationpt_PT
oaire.citation.volume131pt_PT
person.familyNameCastelo-Branco
person.givenNamePedro
person.identifier.ciencia-idE015-7F8F-5CA1
person.identifier.orcid0000-0002-3453-3978
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationbb25b5ad-1769-42be-a7d3-8fe76215aa23
relation.isAuthorOfPublication.latestForDiscoverybb25b5ad-1769-42be-a7d3-8fe76215aa23

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