TERT promoter mutations and monoallelic activation of TERT in cancer

Huang, Franklin W.; Bielski, Craig M.; Rinne, Mikael L.; Hahn, William C.; Sellers, William R.; Stegmeier, Frank; Garraway, Levi A.; Kryukov, Gregory V.

doi:10.1038/oncsis.2015.39

Cited by 87 publications

(113 citation statements)

References 19 publications

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“…Some cancer cell lines show monoallelic expression (MAE) of TERT even in the absence of promoter mutations (Huang et al, 2015). This phenotype suggested that the epigenetic conditions that facilitate TERT expression in these cells might be distinct from those with wt promoters that express TERT biallelically or cancers with promoter mutations.…”

Section: Resultsmentioning

confidence: 99%

“…(B) CCLE WT, wild-type at the TERT promoter. MUT, −124 or −146 TERT promoter mutants, mono_WT, cell lines without known TERT promoter mutations exhibiting monoallelic TERT expression (Huang et al 2015). …”

Section: Supplementary Materialsmentioning

confidence: 99%

“…Multiple cancers show unusual monoallelic activation of TERT by the de novo acquisition of a C>T transition on one TERT promoter (Horn et al, 2013; Huang et al, 2013, 2015; Killela et al, 2013; Stern et al, 2015). These mutations occur at −124 (occasionally at −146) base pairs (bp) from the translational start site and provide a new binding site for the GABPA/B1 transcription factor; the transcriptionally inactive TERT promoter in the same cell bears the H3K27me3 repressive mark (Bell et al, 2015; Stern et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…These mutations occur at −124 (occasionally at −146) base pairs (bp) from the translational start site and provide a new binding site for the GABPA/B1 transcription factor; the transcriptionally inactive TERT promoter in the same cell bears the H3K27me3 repressive mark (Bell et al, 2015; Stern et al, 2015). In many other cancers, TERT is expressed biallelically or monoallelically by molecular mechanisms that remain poorly understood (Huang et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

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Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes

et al. 2017

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SUMMARY A mutation in the promoter of the Telomerase Reverse Transcriptase (TERT) gene is the most frequent noncoding mutation in cancer. The mutation drives unusual monoallelic expression of TERT, allowing immortalization. Here we find that DNA methylation of the TERT CpG Island (CGI) is also allele-specific in multiple cancers. The expressed allele is hypomethylated, which is opposite to cancers without TERT promoter mutations. The continued presence of Polycomb repressive complex 2 (PRC2) on the inactive allele suggests that histone marks of repressed chromatin may be causally linked to high DNA methylation. Consistent with this hypothesis, TERT promoter DNA containing 5-methyl-CpG has much increased affinity for PRC2 in vitro. Thus, CpG methylation and histone marks appear to collaborate to maintain the two TERT alleles in different epigenetic states in TERT promoter-mutant cancers. Finally, in several cancers DNA methylation levels at the TERT CGI correlate with altered patient survival.

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Section: Resultsmentioning

confidence: 99%

Section: Supplementary Materialsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes

et al. 2017

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“…These findings suggest that TERT promoter mutations could be potential mechanisms for TERT reactivation in cancer cells. In more recent studies, investigators found that two highly recurrent point mutations (G228T and G250T) in the TERT promoter might be among the fundamental mechanisms underlying telomerase reactivation/expression in several types of human cancers[149,151-154]. …”

Section: Somatic Mutations In Hccmentioning

confidence: 99%

Genetic alterations in hepatocellular carcinoma: An update

Niu¹,

Niu²,

Wang³

2016

WJG

137

108

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.

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

2020

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Telomerase reverse transcriptase (TERT) is pathologically expressed in the vast majority of human cancers, but the epigenetic regulation of its expression is only beginning to be understood. In particular, the active TERT gene in cancer cells has been characterized as having a hypermethylated CpG island, opposite to the general association of DNA methylation with gene repression. Here, we analyzed TERT promoter CpG methylation in 833 human cancer cell lines representing 23 different tissue types and found hypermethylation of the upstream portion of the CpG island and more conserved hypomethylation of a region including the proximal TERT promoter and exon 1. In cell lines with monoallelic expression of TERT, we found allelic methylation of the proximal TERT promoter. This included cell lines with the À124 or À146 activating promoter mutation as well as wild-type TERT cancer lines. In these cell line types, decreased proximal promoter methylation is associated with the active allele. Compared to cells with monoallelic expression of TERT, lines with biallelic expression of TERT had even lower methylation in the proximal TERT promoter. Thus, in cell lines from cancers of many different tissues, the TERT proximal promoter has canonical DNA methylation, with low methylation correlating with increased TERT expression.

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TERT promoter mutations and monoallelic activation of TERT in cancer

Cited by 87 publications

References 19 publications

Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes

Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes

Genetic alterations in hepatocellular carcinoma: An update

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

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