TERT Promoter Mutations and Risk of Recurrence in Meningioma.
Ontology highlight
ABSTRACT:
SUBMITTER: Sahm F
PROVIDER: S-EPMC4849806 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Unlike patients with World Health Organization (WHO) grade I meningiomas, which are considered benign, patients with WHO grade III meningiomas have very high mortality rates. The principles underlying tumor progression in meningioma are largely unknown, yet a detailed understanding of these mechanisms will be required for effective management of patients with these high grade lethal tumors. We present a case of an intraventricular meningioma that at first presentation displayed remarkable morphologic heterogeneity-composed of distinct regions independently fulfilling histopathologic criteria for WHO grade I, II, and III designations. The lowest grade regions had classic meningothelial features, while the highest grade regions were markedly dedifferentiated. Whereas progression in meningiomas is generally observed during recurrence following radiation and systemic medical therapies, the current case offers us a snapshot of histologic progression and intratumoral heterogeneity in a native pretreatment context. Using whole exome sequencing and high resolution array-based comparative genomic hybridization, we observed marked genetic heterogeneity between the various areas. Notably, in the higher grade regions we found increased aneuploidy with progressive loss of heterozygosity, the emergence of mutations in the TERT promoter, and compromise of ARID1A. These findings provide new insights into intratumoral heterogeneity in the evolution of malignant phenotypes in anaplastic meningiomas and potential pathways of malignant progression.
| S-EPMC4882906 | biostudies-literature
Project description:Abstract INTRODUCTION Telomere-associated constitutional and somatic variants have been associated with etiology and outcome in glioma but have not yet been studied extensively in meningioma. METHODS Constitutional DNA from 275 meningioma patients (Grade I and II) and 1142 controls was evaluated for 1258 preselected telomere associated SNPs using a log-additive model. Odds ratios (OR) and 95% Confidence Intervals were calculated with a Bonferroni-correction applied for multiple testing (p=3.98*10-5). RESULTS SNPs at 4 different loci were significantly associated with increased meningioma risk: 5q23 (rs739719, p=5.75*10-7, OR:2.08), 10q23 (rs9420907; p=3.23*10-6; OR:1.73, rs911547; p=4.31*10-6, OR:1.70), and 12q12 (rs7956602; p=1.85*10-5, OR:1.575, rs1641528; p=2.15*10-6, OR:1.80), and 17p13 (rs4602096; p=1.91*10-5, OR:1.60). SNPS at loci 10q23 (rs2067832; p=2.28*10-5, OR:0.66, rs9325507; p=2.28*10-5; OR:0.66, rs2273698; p=2.28*10-5, OR:0.66, rs11191865; p=3.66*10-5, OR:0.67) were associated with lower incidence of meningioma. CONCLUSIONS These results are the first to identify an association between meningioma risk and TERT and confirm the previously reported association of chr10 with meningioma risk.
| S-EPMC5692414 | biostudies-literature
Project description:BackgroundMeningiomas 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.MethodsFrom 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.ResultsTERT 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.ConclusionTERT promoter mutations drive meningioma aggressiveness, resulting in reduced patient survival, but might also open novel therapeutic options for progressive disease.
| S-EPMC6231195 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, and ranks among the most lethal malignancies globally, primarily due to its high rates of recurrence and metastasis. Despite the urgency, no reliable biomarkers currently exist for predicting tumor recurrence in HCC. Telomerase reverse transcriptase (TERT) promoter mutations (TERTpm) and cellular tumor antigen p53 mutations (TP53m) have been frequently documented in HCC, but their combined clinical significance remains undefined. In this study, we investigated the clinical implications of TERTpm, TP53m, and their co-occurrence in 50 HCC tissue samples using the next-generation sequencing (NGS) technology. We identified TERTpm (C228T) and TP53m in 16 (32%) and 24 (48%) samples, respectively. Our findings indicate that these mutations are more prevalent in male patients (100% for TERTpm, 83.33% for TP53m), in those with solitary tumors (87.5% for both), in individuals with G2-G3 hepatitis (100% / 83.3%), and in cases of moderately differentiated tumors (75.0% / 83.3%). Furthermore, patients with both TERTpm and TP53m exhibited a significantly higher risk of tumor relapse (P<0.05) and shorter progression-free survival (P<0.05). Collectively, our results suggest that presence of both TERTpm and TP53m may serve as a robust predictor of tumor recurrence and a marker of poor prognosis in HCC.
2024-08-01 | GSE273254 | GEO
Project description:Background: Chief among mechanisms of telomerase reverse transcriptase (TERT) reactivation is the appearance of mutations in the TERT promoter. The two main TERT promoter mutations are C>T transitions located -146C>T and -124C>T upstream from the translational start site. They generate a novel Ets/TCF binding site. Both mutations are mutually exclusive and -124C>T is strikingly overrepresented in most cancers. We investigated whether this mutational bias and mutual exclusion could be due to transcriptional constraints. Methods: We compared sense and antisense transcription of a panel of TERT promoter-luciferase vectors harboring the -124C>T and -146C>T mutations alone or together. lncRNA TAPAS levels were measured by RT-PCR. Results: Both mutations generally increased TERT transcription by 2-4-fold regardless of upstream and downstream regulatory elements. The double mutant increased transcription in an additive fashion, arguing against a direct transcriptional constraint. The -146C>T mutation, alone or in combination with -124C>T, also unleashed antisense transcription. In line with this finding, lncRNA TAPAS was higher in cells with mutated TERT promoter (T98G and U87) than in cells with wild-type promoter, suggesting that lncRNA TAPAS may balance the effect of TERT promoter mutations. Conclusions: -146C>T and -124C>T TERT promoter mutations increase TERT sense and antisense transcription, and the double mutant features higher transcription levels. Increased antisense transcription may contain TERT expression within sustainable levels.
| S-EPMC8698883 | biostudies-literature
Project description:Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at-risk primary melanoma patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression-free and melanoma-specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease-free and melanoma-specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease-free survival was 2.3 (95% CI 1.2-4.4) and for melanoma-specific survival 5.8 (95% CI 1.9-18.3). The effect of the mutations on melanoma-specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4-15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1-0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter.
| S-EPMC8238633 | biostudies-literature
Project description:The 2013 discovery of Telomerase reverse transcriptase (TERT) promoter mutations chr5, 1,295,228 C>T (C228T) and 1,295,250 C>T (C250T) in thyroid cancer represents an important event in the thyroid cancer field and much progress has occurred since then. This article provides a comprehensive review of this exciting new thyroid cancer field. The oncogenic role of TERT promoter mutations involves their creation of consensus binding sites for E-twenty-six transcriptional factors. TERT C228T is far more common than TERT C250T and their collective prevalence is, on average, 0, 11.3, 17.1, 43.2 and 40.1% in benign thyroid tumors, papillary thyroid cancer (PTC), follicular thyroid cancer, poorly differentiated thyroid cancer and anaplastic thyroid cancer, respectively, displaying an association with aggressive types of thyroid cancer. TERT promoter mutations are associated with aggressive thyroid tumor characteristics, tumor recurrence and patient mortality as well as BRAF V600E mutation. Coexisting BRAF V600E and TERT promoter mutations have a robust synergistic impact on the aggressiveness of PTC, including a sharply increased tumor recurrence and patient mortality, while either mutation alone has a modest impact. Thus, TERT with promoter mutations represents a prominent new oncogene in thyroid cancer and the mutations are promising new diagnostic and prognostic genetic markers for thyroid cancer, which, in combination with BRAF V600E mutation or other genetic markers (e.g. RAS mutations), are proving to be clinically useful for the management of thyroid cancer. Future studies will specifically define such clinical utilities, elucidate the biological mechanisms and explore the potential as therapeutic targets of TERT promoter mutations in thyroid cancer.
| S-EPMC4750651 | biostudies-literature
Project description:ContextTERT promoter mutations have been associated with adverse prognosis in papillary thyroid carcinomas (PTCs).ObjectiveWe investigated the association between TERT promoter mutations and survival from PTC.DesignRetrospective observational cohort study.PatientsEighty consecutive patients with PTC who underwent surgery between 1990 and 2003.MeasurementsTERT promoter was genotyped in DNA from 80 archival PTCs by Sanger sequencing. Median follow-up was 106 months (range 1-270). Outcomes analysis was stratified according to disease and overall survival status. For each parameter, relative risk (RR) adjusted for age at first surgery and gender was estimated. Both univariate and multivariate analyses were performed using logistic regression, Kaplan-Meier survival analysis and Cox regression models.ResultsPTCs from 11 patients (14%) contained either C228T or C250T TERT promoter mutation. TERT mutations were significantly associated with adverse prognostic features such as older age (P = 0·002), male gender (P = 0·01) and Stage IV disease (P = 0·03). Four patients died from PTC during follow-up: 3 patients with TERT mutations (27%) and one without (1·5%). Disease-related mortality rate with or without TERT mutations was 33·7 vs 1·6 per 1000 patient-years respectively, that is 10 (95% CI = 1·0-104·1, P = 0·05) fold higher, after adjustment for age at first surgery and gender. The combination of TERT promoter mutation and BRAF(V) (600E) significantly increased disease-related death risk (P = 0·002). TERT mutations increased expression of a reporter gene in thyroid cells containing BRAF(V) (600E) .ConclusionsTERT promoter mutations are a major indicator of death due to PTCs. Conversely, absence of TERT mutations portends better survival.
| S-EPMC5683578 | biostudies-literature
Project description:Here we report that promoter mutations in telomerase (TERT), the most common noncoding mutations in cancer, give rise to monoallelic expression of TERT. Through deep RNA sequencing, we find that TERT activation in human cancer cell lines can occur in either mono- or biallelic manner. Without exception, hotspot TERT promoter mutations lead to the re-expression of only one allele, accounting for approximately half of the observed cases of monoallelic TERT expression. Furthermore, we show that monoallelic TERT expression is highly prevalent in certain tumor types and widespread across a broad spectrum of cancers. Taken together, these observations provide insights into the mechanisms of TERT activation and the ramifications of noncoding mutations in cancer.
| S-EPMC4688396 | biostudies-literature
Project description:The reactivation of telomerase reverse transcriptase (TERT) protein is the principal mechanism of telomere maintenance in cancer cells. Mutations in the TERT promoter (TERTp) are a common mechanism of TERT reactivation in many solid cancers, particularly those originating from slow-replicating tissues. They are associated with increased TERT levels, telomere stabilization, and cell immortalization and proliferation. Much effort has been invested in recent years in characterizing their prevalence in different cancers and their potential as biomarkers for tumor stratification, as well as assessing their molecular mechanism of action, but much remains to be understood. Notably, they appear late in cell transformation and are mutually exclusive with each other as well as with other telomere maintenance mechanisms, indicative of overlapping selective advantages and of a strict regulation of TERT expression levels. In this review, we summarized the latest literature on the role and prevalence of TERTp mutations across different cancer types, highlighting their biased distribution. We then discussed the need to maintain TERT levels at sufficient levels to immortalize cells and promote proliferation while remaining within cell sustainability levels. A better understanding of TERT regulation is crucial when considering its use as a possible target in antitumor strategies.
| S-EPMC7140675 | biostudies-literature