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TERT promoter mutations are associated with poor prognosis and cell immortalization in meningioma.

ABSTRACT: Background:Meningiomas are mostly benign tumors tending to progress to higher-grade lesions. Mutations in the telomerase reverse transcriptase (TERT) gene promoter are comparably rare in meningioma, but were recently suggested to predict risk of recurrence and progression. Here we have analyzed a cohort of World Health Organization grades I-III meningiomas regarding the impact of TERT promoter mutations on patient prognosis and in vitro cell propagation feasibility. Methods:From 110 meningioma patients, 128 tissue samples were analyzed for the TERT promoter mutations C228T and C250T by direct sequencing. Of the 128 samples, 121 were tested for cell propagation in vitro. Telomerase activity, TERT mRNA expression, and telomere lengths were investigated by telomeric repeat amplification protocol assay, reverse transcription PCR, and quantitative PCR, respectively. Impact of the E-twenty-six (ETS) transcription factor inhibitor YK-4-279 on cell viability and TERT promoter activity was analyzed. Results:TERT promoter mutations were found in 5.5% of all samples analyzed and were associated with a significantly upregulated telomerase activity and TERT mRNA expression (P < 0.0001 both). Regarding telomere lengths, no significant difference between the TERT promoter wild-type and mutated subgroups was detected. Patients with TERT promoter mutated tumors exhibited significantly shorter overall survival (P = 0.0006; 53.8 vs 115.6 mo). The presence of TERT promoter mutations but not telomerase activity or TERT mRNA expression predicted indefinite cell growth in vitro. TERT promoter mutated meningioma cells were hypersensitive against the ETS transcription factor inhibitor YK-4-279, inducing a distinct downregulation of TERT promoter activity. Conclusion:TERT promoter mutations drive meningioma aggressiveness, resulting in reduced patient survival, but might also open novel therapeutic options for progressive disease.

SUBMITTER: Spiegl-Kreinecker S

PROVIDER: S-EPMC6231195 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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TERT promoter mutations are associated with poor prognosis and cell immortalization in meningioma.

Spiegl-Kreinecker Sabine S Lötsch Daniela D Neumayer Katharina K Kastler Lucia L Gojo Johannes J Pirker Christine C Pichler Josef J Weis Serge S Kumar Rajiv R Webersinke Gerald G Gruber Andreas A Berger Walter W

Neuro-oncology 20181101 12

<h4>Background</h4>Meningiomas are mostly benign tumors tending to progress to higher-grade lesions. Mutations in the telomerase reverse transcriptase (TERT) gene promoter are comparably rare in meningioma, but were recently suggested to predict risk of recurrence and progression. Here we have analyzed a cohort of World Health Organization grades I-III meningiomas regarding the impact of TERT promoter mutations on patient prognosis and in vitro cell propagation feasibility.<h4>Methods</h4>From 1 ...[more]

PMID: 30010853

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Project description:Solitary fibrous tumor is a mesenchymal neoplasm exhibiting a broad spectrum of biological behavior and harboring the NAB2-STAT6 fusion. Clinicopathologic parameters are currently used in risk-prediction models for solitary fibrous tumor, but the molecular determinants of malignancy in solitary fibrous tumors remain unknown. We proposed that the activation of telomere maintenance pathways confers a perpetual malignant phenotype to these tumors. Therefore, we investigated telomerase reverse transcriptase (TERT) reactivation induced by promoter mutations as a potential molecular mechanism for aggressive clinical behavior in solitary fibrous tumor. The retrospective study included tumor samples from 94 patients with solitary fibrous tumor (31 thoracic and 63 extra-thoracic). Follow-up information was available for 68 patients (median, 46 months). TERT promoter mutation analysis was performed by PCR and Sanger sequencing, and TERT mRNA expression was assessed by real-time quantitative reverse transcription PCR. Patients were stratified into clinicopathologic subgroups (high-risk (n=20), moderate-risk (n=28), and low-risk (n=46)) according to the risk-stratification model proposed by Demicco et al. TERT promoter mutations were identified in 26 of 94 (28%) solitary fibrous tumors: -124C>T in 23 tumors (88%), -124C>A in 1 tumor (4%), and -146C>T in 2 tumors (8%). Real-time quantitative reverse transcription PCR revealed that TERT mRNA expression was higher in all solitary fibrous tumors with the mutant TERT promoter than those with the wild-type TERT promoter. TERT promoter mutations were strongly associated with high-risk clinicopathologic characteristics and outcome. An adverse event (relapse, death) occurred in 16 of 68 (24%) patients, 12 with solitary fibrous tumors with TERT promoter mutations and 4 with the wild-type TERT promoter. TERT promoter mutations were strongly associated with older age (P=0.006), larger tumor size (P=0.000002), higher risk classifications (P=2.9 × 10-9), and a worse event-free survival (P=0.0082). Thus, TERT promoter mutations in solitary fibrous tumor influence gene expression and are associated with adverse patient outcome. Integrating TERT promoter mutational status with existing multivariable risk-prediction models might improve risk prediction in patients with solitary fibrous tumor.

Dataset Information

TERT promoter mutations are associated with poor prognosis and cell immortalization in meningioma.

Publications

TERT promoter mutations are associated with poor prognosis and cell immortalization in meningioma.

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