A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study

Castelo‐Branco, Pedro; Leão, Ricardo; Lipman, Tatiana; Campbell, Brittany; Lee, Dong-Hyun; Price, A.; Zhang, Cindy; Heidari, Abolfazl; Stephens, Derek; Boerno, Stefan; Coelho, Hugo; Gomes, Ana; Domingos, Célia; Apolónio, Joana; Schäfer, Georg; Bristow, Robert G.; Schweiger, Michal R.; Hamilton, Robert J.; Zlotta, Alexandre R.; Figueiredo, Arnaldo; Klocker, Helmut; Sültmann, Holger; Tabori, Uri

doi:10.18632/oncotarget.10639

Cited by 61 publications

(76 citation statements)

References 52 publications

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“…Association between higher methylation at cg11625005 and poorer patient survival has been previously reported (Castelo-Branco et al, 2013, 2016; Gojo et al, 2017; Seynnaeve et al, 2017); our results extend these findings to two additional cancer types, suggesting that hypermethylation of the TERT promoter may represent a broadly applicable prognostic marker. To our knowledge, our data showing a more positive outcome for stomach adenocarcinoma patients with higher methylation at cg11625005 or with high EZH2 expression and suggest that the mechanisms driving survival in these patients may be distinct.…”

Section: Discussionsupporting

confidence: 89%

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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: Discussionsupporting

confidence: 89%

“…Methylation levels at cg11625005 are negatively correlated with patient survival in some cancers (Castelo-Branco et al, 2013, 2016; Gojo et al, 2017). We therefore analyzed overall survival (OS) with respect to methylation and TERT promoter mutation in patient samples for a range of cancers within the TCGA.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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“…In UBC, TERT p Mut is an early event while THOR hypermethylation is associated with disease progression and increased TERT expression. This pattern has been observed in other cancer types …”

Section: Discussionsupporting

confidence: 84%

“…Our group and others have identified a parallel epigenetic control of telomerase activation in cancer. Specifically, a region located upstream of the core mutation area, within the TERT promoter, termed THOR ( TERT Hypermethylated Oncological Region) is hypermethylated in many TERT‐expressing cancers, is associated with telomerase activation and predicts clinical outcomes in multiple tumor types . We therefore hypothesized that dual mechanisms activate telomerase in UBC.…”

Section: Introductionmentioning

confidence: 99%

Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer

Leão

Lee

Figueiredo

et al. 2018

Intl Journal of Cancer

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In urothelial bladder cancer (UBC), risk stratification remains an important unmet need. Limitless self‐renewal, governed by TERT expression and telomerase activation, is crucial for cancer progression. Thus, telomerase activation through the interplay of mutations ( TERT p Mut ) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERT p Mut and the TERT Hypermethylated Oncological Region (THOR) status on telomerase activation and patient outcome in a UBC international cohort ( n = 237). We verified that TER Tp Mut were frequent (76.8%) and present in all stages and grades of UBC. Hypermethylation of THOR was associated with higher TERT expression and higher‐risk disease in nonmuscle invasive bladder cancers (NMIBC). TERT p Mut alone predicted disease recurrence (HR: 3.18, 95%CI 1.84 to 5.51, p < 0.0001) but not progression in NMIBC. Combined THOR high / TER Tp Mut increased the risk of disease recurrence (HR 5.12, p < 0.0001) and progression (HR 3.92, p = 0.025). Increased THOR hypermethylation doubled the risk of stage progression of both TERT p wt and TERT p Mut NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERT p Mut is an early event in bladder carcinogenesis THOR hypermethylation is a dynamic process that contributes to disease progression. While the absence of alterations comprises an extremely indolent phenotype, the combined genetic and epigenetic alterations of TERT bring additional prognostic value in NMIBC and provide a novel insight into telomere biology in cancer.

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“…showed that coexistence of TERT promoter and BRAF or NRAS mutations was associated with a 2-fold reduced rate of disease-free survival and a 5-fold reduced rate of melanoma-specific survival in patients with stage I and II melanoma26. TERT promoter hypermethylation is also an effective molecular marker for prognosis in a number of cancer types, and was previously shown to correlate with increased TERT expression in a subset of melanomas2933373839.…”

Section: Discussionmentioning

confidence: 98%

Genetic and Epigenetic Alterations of TERT Are Associated with Inferior Outcome in Adolescent and Young Adult Patients with Melanoma

Seynnaeve

Lee

Borah

et al. 2017

Sci Rep

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Progression of melanoma to distant sites in adolescents and young adults (AYAs) is not reliably predicted by clinicopathologic criteria. TERT promoter mutations when combined with BRAF/NRAS mutations correlate with adverse outcome in adult melanoma. To determine the prognostic value of TERT alterations in AYA melanoma, we investigated the association of TERT promoter mutations, as well as promoter methylation, an epigenetic alteration also linked to TERT upregulation, with TERT mRNA expression and outcome using a well-characterized cohort of 27 patients with melanoma (ages 8–25, mean 20). TERT mRNA expression levels were significantly higher in tumors harboring TERT promoter mutation and/or hypermethylation than those without either aberration (P = 0.046). TERT promoter mutations alone did not predict adverse outcomes (P = 0.50), but the presence of TERT promoter methylation, alone or concurrent with promoter mutations, correlated with reduced recurrence-free survival (P = 0.001). These data suggest that genetic and epigenetic alterations of TERT are associated with TERT upregulation and may predict clinical outcomes in AYA melanoma. A more exhaustive understanding of the different molecular mechanisms leading to increased TERT expression may guide development of prognostic assays to stratify AYA melanoma patients according to clinical risk.

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A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study

Cited by 61 publications

References 52 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

Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer

Genetic and Epigenetic Alterations of TERT Are Associated with Inferior Outcome in Adolescent and Young Adult Patients with Melanoma

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