DNA hypermethylation within TERT promoter upregulates TERT expression in cancer

Lee, Donghyun D.; Leão, Ricardo; Komosa, Martin; Gallo, Marco; Zhang, Cindy H.; Lipman, Tatiana; Remke, Marc; Heidari, Abolfazl; Nunes, Nuno Miguel; Apolónio, Joana; Price, A.; Mello, Ramon Andrade De; Dias, João S.; Huntsman, David; Hermanns, Thomas; Wild, Peter J.; Vanner, Robert; Zadeh, Gelareh; Karamchandani, Jason; Das, Sunit; Taylor, Michael D.; Hawkins, Cynthia; Wasserman, Jonathan D.; Figueiredo, Arnaldo; Hamilton, Robert J.; Minden, Mark D.; Wani, Khalida; Diplas, Bill H.; Yan, Hai; Aldape, Kenneth; Akbari, Mohammad Reza; Danesh, Arnavaz; Pugh, Trevor J.; Dirks, Peter B.; Castelo‐Branco, Pedro; Tabori, Uri

doi:10.1172/jci121303

Cited by 139 publications

(123 citation statements)

References 29 publications

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“…Cancer cells are commonly characterised by hypermethylation of promoter CpG islands resulting in repression of tumour suppressor genes. However, in TERT , promoter hypermethylation was found to be associated with higher expression, since CTCF repressors of TERT transcription do not bind methylated sequences [3, 16, 17, 19]. In our sample cohort, there was no correlation between TERT methylation of cg11625005 and mRNA expression (n=34, Fig 3 and an overview in Fig 7C).…”

Section: Resultsmentioning

confidence: 74%

“…In contrast to most genes, methylation of the TERT p positively correlates with its mRNA expression [3, 16, 17, 19]. Although we were not able to confirm this finding, we investigated whether besides promoter methylation, other mechanisms could contribute to chromatin accessibility to transcription factors affecting TERT p regulation.…”

Section: Resultsmentioning

confidence: 86%

“…In stark contrast to most genes, TERT p hypermethylation may also allow gene expression since transcriptional repressors rely on unmethylated promoter CpGs, such as CCCTC-binding factor (CTCF)/cohesin complex or MAZ [16-18]. As such, in combination with transcription factor binding, dissociation of the repressor may result in TERT expression [3, 16, 19, 20]. Castelo-Branco et al proposed that methylation of a specific CpG site in TERT p, cg11625005 (position 1,295,737 in hg19) was associated with paediatric brain tumours progression and poor prognosis [20].…”

Section: Introductionmentioning

confidence: 99%

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Interplay betweenTERTpromoter mutations and methylation culminates in chromatin accessibility andTERTexpression

Salgado

Roelse

Nell

et al. 2019

Preprint

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AbstractThe telomerase reverse transcriptase (TERT) gene is responsible for telomere maintenance in germline and stem cells, and is re-expressed in 90% of human cancers. Contrary to common concepts, CpG methylation in the TERT promoter (TERTp), was correlated with TERT mRNA expression. Furthermore, two hotspot mutations in TERTp, dubbed C228T and C250T, have been revealed to assist binding of transcription factor ETS/TCF and subsequent TERT expression. This study aimed to elucidate the combined contribution of epigenetic (promoter methylation and higher-order chromatin structure) and genetic (promoter mutations) mechanisms in regulating TERT gene expression in healthy skin and in melanoma cell lines (n=61). We unexpectedly observed that the methylation of TERTp was as high in a subset of healthy skin cells, mainly keratinocytes, as in cutaneous melanoma cell lines. In spite of the high promoter methylation fraction in wild-type (WT) samples, TERT mRNA was only expressed in the melanoma cell lines with high methylation or intermediate methylation in combination with TERT mutations. TERTp methylation was positively correlated with chromatin accessibility and expression in 8 melanoma cell lines. Cooperation between epigenetic and genetic mechanisms were best observed in heterozygous mutant cell lines as chromosome accessibility preferentially concerned the mutant allele. Combined, these results suggest a complex model in which TERT expression requires either a widely open chromatin state throughout the promoter in TERTp-WT samples due to high methylation or a combination of moderate methylation fraction/chromatin accessibility in the presence of the C228T/C250T mutations.Author summaryPvdV and RvD formulated research goals and aims and supervised the overall progress. Wet-lab experiments, preparation of the manuscript and statistical analysis were performed by CS and CR. CS designed the novel assays. RN was involved in the experimental setup. RvD, NG and PvdV were responsible for funding acquisition. CR, RN, NG, RvD and PvdV critically reviewed the manuscript.

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Section: Resultsmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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Interplay betweenTERTpromoter mutations and methylation culminates in chromatin accessibility andTERTexpression

Salgado

Roelse

Nell

et al. 2019

Preprint

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“…We also investigated THOR region where methylation of CpG sites is generally associated with increased TERT expression 16,36 . However, our data show that increased TERT expression in BCC tumors can be primarily attributed to the promoter mutations as shown in adult gliomas 37 .…”

Section: Discussionmentioning

confidence: 99%

Coding and noncoding somatic mutations in basal cell carcinoma

Maturo

Rachakonda

Heidenreich

et al. 2019

Preprint

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Basal cell carcinoma (BCC) represents the most commonly diagnosed human cancer among persons of European ancestry with etiology mainly attributed to sun-exposure. In this study we investigated mutations in coding and flanking regions of the PTCH1 and TP53 genes and noncoding alterations in the TERT and DPH3 promoters in 191 BCC tumors. In addition, we measured CpG methylation within the TERT hypermethylated oncological region (THOR) and transcriptions levels of the reverse transcriptase subunit. We observed mutations in PTCH1 in 59% and TP53 in 31% of the tumors. Noncoding mutations in TERT and DPH3 promoters were detected in 59% and 38% of the tumors, respectively. We observed a statistically significant co-occurrence of mutations at the four investigated loci. While PTCH1 mutations tended to associate with decreased patient age at diagnosis; TP53 mutations were associated with light skin color and increased number of nevi; TERT and DPH3 promoter with history of cutaneous neoplasms in BCC patients. TERT promoter mutations but not THOR methylation associated with an increased expression of the reverse transcriptase subunit.Our study signifies, in addition to the protein altering mutations in the PTCH1 and TP53 genes, the importance of noncoding mutations in BCC, particularly functional alterations in the TERT promoter. Introduction,

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“…On the one hand, hypermethylation of a small cluster of CpG dinucleotides upstream of the TERT transcriptional start site (TSS) was implicated in conferring activation of TERT expression in cancer (20,21) . However, other studies, including a study examining DNA methylation in cancers with promoter mutations, revealed that TERT promoter methylation behaved in the canonical fashion, with promoter methylation associated with silenced alleles, and lack of promoter methylation associated with expressed alleles (22,23) .…”

Section: Introductionmentioning

confidence: 99%

Pervasive promoter hypermethylation of silencedTERTalleles in human cancers

Esopi

Graham

Brosnan-Cashman

et al. 2020

Preprint

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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 telomerase gene expression, even in the context of activating hotspot promoter mutations (C228T and C250T).The role of epigenetic mechanisms, including DNA methylation, in regulating telomerase gene expression in cancer cells is not fully understood. 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. 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 observe 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. Our findings suggest that hypermethylation of the TERT promoter alleles signals transcriptional repression of those alleles, leading to the attenuation of TERT activation in cancer cells. SIGNIFICANCEHypermethylation of the TERT promoter alleles to attenuate TERT activation in cancer cells may account for the modest activation of TERT expression in most cancers.

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DNA hypermethylation within TERT promoter upregulates TERT expression in cancer

Cited by 139 publications

References 29 publications

Interplay betweenTERTpromoter mutations and methylation culminates in chromatin accessibility andTERTexpression

Interplay betweenTERTpromoter mutations and methylation culminates in chromatin accessibility andTERTexpression

Coding and noncoding somatic mutations in basal cell carcinoma

Pervasive promoter hypermethylation of silencedTERTalleles in human cancers

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