Preclinical and clinical implications of TERT promoter mutation in glioblastoma multiforme

Jeong, Da Eun; Woo, Seon Rang; Nam, Hyunwoo; Nam, Do‐Hyun; Lee, Jae Ho; Joo, Kyeung Min

doi:10.3892/ol.2017.7196

Cited by 15 publications

(18 citation statements)

References 33 publications

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“…For example, a negative relationship was observed between telomerase activity and clinical outcome in breast cancer, colorectal cancer and gastrointestinal stromal tumors [ 38 , 40 , 41 ]. In gliomas, TERT promoter mutations lead to higher telomerase activity [ 42 ] but the associations between TERT promoter mutations and clinical outcomes are still controversial [ 43 , 44 ]. In the Short TL group, more cancer types also showed significantly different survival probabilities ( Figure S7 ).…”

Section: Resultsmentioning

confidence: 99%

Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

Sung

Lim

Joung

et al. 2020

Cancers

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Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that extends telomeres in cancer cells. It influences tumorigenesis and patient survival. Despite the clinical significance of ALT in tumors, the manner in which ALT is activated and influences prognostic outcomes in distinct cancer types is unclear. In this work, we profiled distinct telomere maintenance mechanisms (TMMs) using 8953 transcriptomes of 31 different cancer types from The Cancer Genome Atlas (TCGA). Our results demonstrated that approximately 29% of cancer types display high ALT activity with low telomerase activity in the telomere-lengthening group. Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe. Five cancer types showed a significant difference in survival in the presence of high ALT activity. Sarcoma patients with elevated ALT had unfavorable risks (p < 0.038) coupled with a high expression of TOP2A, suggesting this as a potential drug target. On the contrary, glioblastoma patients had favorable risks (p < 0.02), and showed low levels of antigen-presenting cells. Together, our analyses highlight cancer type-dependent TMM activities and ALT-associated genes as potential therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

Sung

Lim

Joung

et al. 2020

Cancers

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“…TERT promoter muts attract transcriptional factors that should not normally act at this site and thus contribute to the activation of TERT expression [26]. TERT muts have originally been associated with tumors of low self-renewal [19] including GBMs; in the latter, TERT muts increase the capacity of self-renewal and thus survival and growth [28], despite the fact that they do not contribute to increased size of the telomeres [26]. Previously, TERT promoter muts were shown to interact with IDH muts conferring a dual prognostic impact [11,29].…”

Section: Discussionmentioning

confidence: 99%

Is There an Independent Role of TERT and NF1 in High Grade Gliomas?

Razis

Kotoula

Koliou

et al. 2020

Translational Oncology

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BACKGROUND: High grade glioma molecular profiling is of particular interest in neurooncology. The role of telomerase reverse transcriptase (TERT) varies dependent upon other molecular parameters. We explored the role of TERT in 101 high-grade gliomas. METHODS: A total of 101 patients (pts) with grade III–IV gliomas treated with standard of care and informative tumor genotypes were included in the present study. Of 55 genes targeted with the next-generation sequencing panel, mutations (muts) were found in 37; these were included in the analysis. TERT mut were tested with Sanger sequencing. MGMT promoter methylation status was determined by methylation specific PCR. RESULTS: 270 mut were detected in 92/101 tumors (91.1%). TERT was the most frequently mutated gene (74.3%). IDH1/2 mut were mutually exclusive with mut in the neurofibromin 1 (NF1) gene. Mutated TERT was associated with wild-type (wt) IDH1/2 (p = 0.025). The 12-month overall survival (OS) rate was 74.3% (median OS: 22 months). Pts with TERT and NF1 wt had a median OS of 40.8 months, while among pts with NF1 wt/TERT mutant, the median OS was 18.5 months. NF1 and TERT mut univariately conferred shorter OS (HR = 3.19; p = 0.004 and HR = 2.28; p = 0.002). Upon multivariate analysis, mutated TERT showed marginal unfavorable prognostic significance for OS (p = 0.049), while NF1 lost its unfavorable significance (p = 0.151). CONCLUSIONS: TERT is herein proven to confer poor prognosis in high grade gliomas, independent of IDH and MGMT. NF1 seems to also confer poor prognosis although our small numbers do not allow for firm conclusions.

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“…5 In vitro studies have demonstrated a strong association between the presence of TERT mutations and sphere-forming capacity of GBM cells. 21 An extensive network of transcription factors has been demonstrated to be involved in TERT regulation, with increasing evidence of TERT involvement in the regulation of downstream cellular processes such as cellular signaling and cell cycle regulation. 6 In squamous cell carcinoma, TERT downregulation was shown to result in decreased expression of matrix metalloproteinases.…”

Section: Discussionmentioning

confidence: 99%

“…TERT promoter mutations occur commonly in primary GBM and are associated with worse prognosis . In vitro studies have demonstrated a strong association between the presence of TERT mutations and sphere‐forming capacity of GBM cells . An extensive network of transcription factors has been demonstrated to be involved in TERT regulation, with increasing evidence of TERT involvement in the regulation of downstream cellular processes such as cellular signaling and cell cycle regulation .…”

Section: Discussionmentioning

confidence: 99%

MRI Features Associated with TERT Promoter Mutation Status in Glioblastoma

Ivanidze

Lum

Pisapia

et al. 2019

Journal of Neuroimaging

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BACKGROUND AND PURPOSE Telomerase reverse transcriptase (TERT) promoter mutations are associated with worse prognosis in glioblastoma. The purpose of this study was to evaluate whether TERT mutation status was associated with specific morphologic and quantitative imaging features. METHODS Twenty‐nine patients with isocitrate dehydrogenase 1/2‐wildtype glioblastoma (13 TERT‐wildtype, 16 TERT‐mutated), who underwent preoperative magnetic resonance (MR) imaging were included in this retrospective study. Qualitative imaging phenotypes were evaluated using the Visually Accessible Rembrandt Images (VASARIs) feature set. Histogram analysis of apparent diffusion coefficient (ADC) and dynamic contrast‐enhanced MR perfusion values were performed on enhancing tumor volumes‐of‐interest, and differences between TERT‐wildtype and TERT‐mutated tumors were assessed. RESULTS VASARI analysis demonstrated that the majority of morphologic features were not significantly different between TERT‐wildtype and TERT‐mutated tumors, although a higher proportion of TERT‐wildtype tumors featured nonenhancing tumor crossing midline (P = .014). TERT‐mutated tumors demonstrated lower median rate constant kep (.38 vs. .76, P = .03) and lower median volume transfer coefficient Ktrans (.13 vs. .31, P = .02). There was no significant difference in median plasma volume vp (P = .92) or ADC values (P = .66) between the two groups. We further found a significant interaction between median kep and Ktrans and TERT status, respectively, suggesting greater risk of death with increasing blood‐brain barrier dysfunction in TERT‐mutated but not in TERT‐wildtype tumors. CONCLUSION Our study demonstrates evidence of altered permeability metrics associated with TERT mutation in glioblastoma, laying the foundation for future prospective studies assessing implications for therapeutic management and clinical outcomes.

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Preclinical and clinical implications of TERT promoter mutation in glioblastoma multiforme

Cited by 15 publications

References 33 publications

Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

Is There an Independent Role of TERT and NF1 in High Grade Gliomas?

MRI Features Associated with TERT Promoter Mutation Status in Glioblastoma

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