Allele‐specific proximal promoter hypomethylation of the telomerase reverse transcriptase gene (<i>TERT</i>) associates with <i>TERT</i> expression in multiple cancers

Rowland, Teisha J.; Bonham, Andrew J.; Cech, Thomas R.

doi:10.1002/1878-0261.12786

Cited by 24 publications

(43 citation statements)

References 49 publications

(106 reference statements)

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“…In recent investigations led in a variety of cancer cells expressing hTERT, the distal promoter region of hTERT was recurrently observed hypermethyladed (16,17). Therefore hTERT distal promoter DNA hypermethylation was associated with hTERT re-expression in cancer cells and proposed as a potential biomarker (7,12,15,16).…”

Section: Discussionmentioning

confidence: 99%

“…However, in some solid tumors, and in hematological disorders like non-Hodgkin lymphomas including CTCL, these known genetic alterations are rare (36,37). Additionally, the mechanism responsible for hTERT re- Since hTERT promoter DNA is dense in CpG islands (figure 2A), numerous studies explored the role of hTERT promoter methylation in hTERT expression (11,(15)(16)(17). A recent review of the literature mentioned that hTERT promoter does not behave in a simplistic manner (24).…”

Section: Discussionmentioning

confidence: 99%

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Exploring hTERT promoter methylation in cutaneous T‐cell lymphomas

et al. 2021

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Cutaneous T-cell lymphomas (CTCL) are telomerase-positive tumors expressing hTERT, although neither gene rearrangement/amplification nor promoter hotspot mutations could explain the hTERT re-expression. As the hTERT promoter is rich in CpG, we investigated the contribution of epigenetic mechanisms in its reexpression. We analyzed hTERT promoter methylation status in CTCL cells compared to healthy cells. Gene-specific methylation analyses revealed a common methylation pattern exclusively in tumor cells. This methylation pattern encompassed a hypermethylated distal region from-650bp to-150bp and a hypomethylated proximal region from-150bp to +150bp. Interestingly, the hypermethylated region matches with the recently named TERT Hypermethylated Oncogenic Region (THOR). THOR has been associated with telomerase reactivation in many cancers, but it has so far not been reported in cutaneous lymphomas. Additionally, we assessed the effect on THOR of two histone deacetylase inhibitors (HDACi), romidepsin and vorinostat, both approved for CTCL treatment as well as a DNA methyltransferase inhibitor (DNMTi) 5-azacytidine, unapproved for CTCL. Contrary to our expectations, the findings reported herein revealed that THOR methylation is relatively stable under these epigenetic drugs' pressure, whereas these drugs reduced the hTERT gene expression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exploring hTERT promoter methylation in cutaneous T‐cell lymphomas

et al. 2021

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“…In contrast, TERTp wild-type cell lines tended to lack ASM throughout the TERT locus, instead being hypermethylated in all regions except for exon 1 (Fig. 4b), and partial hypomethylation in promoter mutants may reflect the hemizygous methylation previously observed at the TERT locus (Rowland et al, 2020;Stern et al, 2015Stern et al, , 2017.…”

Section: Distinct Tertp Methylation Patterns At the Tert Locusmentioning

confidence: 80%

Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines

Ghandi

Huang

2021

Preprint

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In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer Project, we calculated telomere content across 1,299 cancer cell lines. We find that telomerase reverse transcriptase (TERT) expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance components. Increased dependencies of shelterin members are associated with wild-type TP53 status. Investigating the epigenetic regulation of TERT, we find widespread allele-specific expression in promoter-wildtype contexts. TERT promoter-mutant cell lines exhibit hypomethylation at PRC2-repressed regions, suggesting a cooperative global epigenetic state in the reactivation of telomerase. By incorporating telomere content with genomic features across comprehensively characterized cell lines, we provide further insights into the role of telomere regulation in cancer immortality.

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“…The detection of recurrent genetic alterations associated with repeat preservation at chromosomal ends through large-scale pan-cancer whole-genome studies has highlighted the importance of the telomere maintenance mechanism in cancers 53,54 . Telomerase reactivation in tumors occurs through several mechanisms, including amplification, rearrangements, viral integrations, and promoter methylation at the locus leading to increased TERT transcription [55][56][57][58][59][60] . The discovery of the mutations within the core promoter of the TERT gene, described as a milestone in telomere biology, afforded a definite mechanism of telomerase upregulation [61][62][63] .…”

Section: Introductionmentioning

confidence: 99%

Occurrence, functionality, and abundance of theTERTpromoter mutations

Rachakonda

Hoheisel

Kumar

2021

Preprint

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Telomere shortening at chromosomal ends due to the constraints of the DNA replication process acts as a tumor suppressor by restricting the replicative potential in primary cells. Cancers evade that limitation primarily through rejuvenation of telomerase via different mechanisms. Mutations within the promoter of the telomerase reverse transcriptase (TERT) gene define a definite method for the ribonucleic enzyme regeneration predominantly in cancers that arise from tissues with low rates of self-renewal. The promoter mutations cause a moderate surge in TERT transcription and telomerase rejuvenation to the levels sufficient to delay replicative senescence but not prevent bulk telomere shortening and genomic instability. Since the discovery, a staggering number of studies and publications have resolved the discrete aspects, effects, and clinical relevance of the TERT promoter mutations. Those noncoding alterations link the TERT transcription with oncogenic pathways, associate with markers of poor outcome, and define patients with reduced survivals in several cancers. In this review, we discuss the occurrence and impact of the promoter mutations and highlight the mechanism of TERT activation. We further deliberate on the foundational question of the abundance of the TERT promoter mutations and a general dearth of functional mutations within noncoding sequences as evident from pan-cancer analysis of the whole-genomes. We posit that the favorable genomic constellation within the TERT promoter may be less than a common occurrence in other noncoding functional elements and the evolutionary constraints limit the functional fraction within the human genome, hence the lack of abundant mutations outside the coding sequences.

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Allele‐specific proximal promoter hypomethylation of the telomerase reverse transcriptase gene (TERT) associates with TERT expression in multiple cancers

Cited by 24 publications

References 49 publications

Exploring hTERT promoter methylation in cutaneous T‐cell lymphomas

Exploring hTERT promoter methylation in cutaneous T‐cell lymphomas

Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines

Occurrence, functionality, and abundance of theTERTpromoter mutations

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