TERT Promoter Alterations in Glioblastoma: A Systematic Review.
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ABSTRACT:
SUBMITTER: Olympios N
PROVIDER: S-EPMC7962450 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH). These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX-mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, about 20% of glioblastomas lack alterations in TERTp and IDH. These tumors, designated TERTpWT-IDHWT glioblastomas, do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we report the genetic landscape of TERTpWT-IDHWT glioblastoma and identify SMARCAL1 inactivating mutations as a novel genetic mechanism of ALT. Furthermore, we identify a novel mechanism of telomerase activation in glioblastomas that occurs via chromosomal rearrangements upstream of TERT. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDHWT-TERTSV), and an ALT-positive subgroup (IDHWT-ALT) with mutations in ATRX or SMARCAL1.
| S-EPMC5970234 | biostudies-literature
Project description:The catalytic activity of human Telomerase Reverse Transcriptase (TERT) compensates for the loss of telomere length, eroded during each cell cycle, to ensure a correct division of stem and germinal cells. In human tumors, ectopic TERT reactivation, most frequently due to hotspot mutations in the promoter region (TERTp), i.e. c.1-124 C?>?T, c.1-146 C?>?T, confers a proliferative advantage to neoplastic cells. In gliomas, TERTp mutations (TERTpmut) mainly occur in oligodendroglioma and glioblastoma. We screened, for TERTp hotspot mutations, 301 adult patients with gliomas and identified heterozygous mutations in 239 cases: 94% of oligodendroglioma, 85% of glioblastoma, and 37.5% of diffuse/anaplastic astrocytoma. Besides the recurrent c.1-124 C?>?T and c.1-146 C?>?T, two cases of glioblastoma harbored novel somatic TERTp variants, which consisted of a tandem duplications of 22 nucleotides, i.e. a TERTp c.1-100_1-79dup and TERTp c.1-110_1-89, both located downstream c.1-124 C?>?T and c.1-146 C?>?T. In silico analysis predicted the formation of 119 and 108 new transcription factor's recognition sites for TERTp c.1-100_1-79dup and TERTp c.1-110_1-89, respectively. TERTp duplications (TERTpdup) mainly affected the binding capacity of two transcription factors' families, i.e. the members of the E-twenty-six and the Specificity Protein/Krüppel-Like Factor groups. In fact, these new TERTpdup significantly enhanced the E-twenty-six transcription factors' binding capacity, which is also typically increased by the two c.1-124 C?>?T/c.1-146 C?>?T hotspot TERTpmut. On the other hand, they were distinguished by enhanced affinity for the Krüppel proteins. The luciferase assay confirmed that TERTpdup behaved as gain-of-function mutations causing a 2,3-2,5 fold increase of TERT transcription. The present study provides new insights into TERTp mutational spectrum occurring in central nervous system tumors, with the identification of new recurrent somatic gain-of-function mutations, occurring in 0.8% of glioblastoma IDH-wildtype.
| S-EPMC7445914 | biostudies-literature
Project description:Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNP's, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.
| S-EPMC4599297 | biostudies-literature
Project description:Cancer is a genetic disease caused by changes in gene expression resulting from somatic mutations and epigenetic changes. Although the probability of mutations is proportional with cell number and replication cycles, large bodied species do not develop cancer more frequently than smaller ones. This notion is known as Peto's paradox, and assumes stronger tumor suppression in larger animals. One of the possible tumor suppressor mechanisms involved could be replicative senescence caused by telomere shortening in the absence of telomerase activity. We analysed telomerase promoter activity and transcription factor binding in mammals to identify the key element of telomerase gene inactivation. We found that the GABPA transcription factor plays a key role in TERT regulation in somatic cells of small rodents, but its binding site is absent in larger beavers. Protein binding and reporter gene assays verify different use of this site in different species. The presence or absence of the GABPA TF site in TERT promoters of rodents correlates with TERT promoter activity; thus it could determine whether replicative senescence plays a tumor suppressor role in these species, which could be in direct relation with body mass. The GABPA TF binding sites that contribute to TERT activity in somatic cells of rodents are analogous to those mutated in human tumors, which activate telomerase by a non-ALT mechanism.
| S-EPMC7704627 | biostudies-literature
Project description:The promoter region of the telomerase reverse transcriptase gene (TERT) is mutated in a subpopulation of patients with glioblastoma multiforme (GBM). In the present study, preclinical and clinical implications of the mutation were analyzed in 25 GBMs to evaluate its utility as a therapeutic target. Associations between the TERT promoter mutation and a number of preclinical/clinical characteristics were analyzed. Notably, the TERT promoter mutation was identified in 92.3% of GBMs where dissociated cells revealed in vitro sphere formation capacity; while the TERT promoter mutation was identified in 33.3% of GBMs without in vitro sphere formation capacity (P=0.004). In addition, this significantly increased mutation rate was observed in GBMs with in vivo tumorigenic potential (80% vs. 0%; P=0.004). Furthermore, patients with GBM exhibiting the TERT promoter mutation demonstrated significantly decreased overall survival rate compared with patients lacking this mutation (81.7 vs. 152.6 weeks; P=0.026). The results of the present study indicated that the TERT promoter mutation is associated with the self-renewal capacity of GBM cells and clinical aggressiveness of GBMs, which may be translated to a targeting therapy against TERT to inhibit the self-renewal of GBM cells.
| S-EPMC5755188 | biostudies-other
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:BACKGROUND:The association between telomerase reverse transcriptase (TERT) promoter mutations and some clinical behaviors in thyroid cancer remains controversial and requires additional investigation. This study aimed to evaluate the association between TERT promoter mutations and clinical behaviors (including clinicopathological features and prognosis) in differentiated thyroid carcinomas (DTC). METHODS:We performed an up-to-date systematic review and current comprehensive meta-analysis. We searched three electronic databases for relevant studies. We used fixed- or random-effect models to calculate pooled estimated odds ratios (ORs) or standardized mean differences (SMDs) and corresponding 95% confidence intervals (CIs). RESULTS:We included 51 eligible studies incorporating 11,382 cases. Average frequencies of TERT promoter mutations in DTC, papillary (PTC), and follicular (FTC) thyroid carcinomas were 10.9%, 10.6%, and 15.1%, respectively. In DTC and PTC, TERT promoter mutations were significantly associated with sex, age, tumor size, vascular invasion, extrathyroidal extension, lymph node and distant metastases, advanced tumor, nodes, and metastasis (TNM) stage, persistence/recurrence, and disease-specific mortality. In FTC, TERT promoter mutations were significantly associated with age, distant metastases, advanced TNM stage, persistence/recurrence, and disease-specific mortality. CONCLUSIONS:TERT promoter mutations could be considered as biomarkers assisting in risk stratification, prognostic prediction, and individualizing therapeutic options for DTC (PTC and FTC).
| S-EPMC6969012 | biostudies-literature
Project description:The clinical implications of plasmatic cell-free and tumor DNA (cfDNA and ctDNA) are challenging in glioblastoma. This prospective study included 52 consecutive newly diagnosed glioblastoma (n = 49) or gliosarcoma (n = 3) patients treated with concomitant temozolomide and radiotherapy (RT-TMZ), followed by a TMZ maintenance phase. Plasma samples were collected at baseline, before RT-TMZ (pre-RT-TMZ) and at the end of adjuvant TMZ, or at the time of progression in cases of progressive disease (PD). The cfDNA concentration was measured with a fluorometric method, and ctDNA was detected using targeted droplet digital PCR. The main objectives were to analyze the associations between cfDNA and ctDNA measurements during the course of treatment with PD and survival. There was a significant decrease in median cfDNA concentration from baseline to pre-RT-TMZ-19.4 versus 9.7 ng/mL (p < 0.0001)-in the entire cohort. In patients with PD, a significant increase in cfDNA concentration from pre-RT-TMZ to time of PD was observed, from 9.7 versus 13.1 ng/mL (p = 0.037), respectively, while no difference was observed for nonprogressive patients. Neither the cfDNA concentration at baseline nor its kinetics correlated with survival. ctDNA was detected in 2 patients (3.8%) and only in gliosarcoma subtypes.Trial registration ClinicalTrial, NCT02617745. Registered 1 December 2015, https://clinicaltrials.gov/ct2/show/NCT02617745?term=glioplak&draw=2&rank=1 .
| S-EPMC7641818 | biostudies-literature
Project description:Despite decades of intense research, the complex biology of glioblastoma (GBM) is not completely understood. Progression-free survival and overall survival have remained unchanged since the implementation of the STUPP regimen in 2005 with concomitant radio-/chemotherapy and adjuvant chemotherapy with temozolomide. In the context of Hanahan and Weinberg's six hallmarks and two emerging hallmarks of cancer, we discuss up-to-date status and recent research in the biology of GBM. We discuss the clinical impact of the research results with the most promising being in the hallmarks 'enabling replicative immortality', 'inducing angiogenesis', 'reprogramming cellular energetics' and 'evading immune destruction'. This includes the importance of molecular diagnostics according to the new WHO classification and how next generation sequencing is being implemented in the clinical daily life. Molecular results linked together with clinical outcome have revealed the importance of the prognostic biomarker isocitratedehydrogenase (IDH), which is now part of the diagnostic criteria in brain tumours. IDH is discussed in the context of the hallmark 'reprogramming cellular energetics'. O-6-methylguanine-DNA methyltransferase status predicts a more favourable response to treatment and is thus a predictive marker. Based on genomic aberrations, Verhaak et al have suggested a division of GBM into three subgroups, namely, proneural, classical and mesenchymal, which could be meaningful in the clinic and could help guide and differentiate treatment decisions according to the specific subgroup. The information achieved will develop and improve precision medicine in the future.
| S-EPMC5419216 | biostudies-other
Project description:BackgroundPromoter mutation in the human telomerase reverse transcriptase gene (hTERT) occurs in ~75% of primary glioblastoma (GBM). Although the mutation appears to upregulate telomerase expression and contributes to the maintenance of telomere length, its clinical significance remains unclear.MethodsWe performed hTERT promoter genotyping on 303 isocitrate dehydrogenase 1 wild-type GBM tumors treated with standard chemoradiotherapy. We also stratified 190 GBM patients from the database of The Cancer Genome Atlas (TCGA) by hTERT gene expression. We analyzed overall and progression-free survival by Kaplan-Meier and Cox regression.ResultsWe detected hTERT promoter mutation in 75% of the patients. When included as the only biomarker, hTERT mutation was not prognostic in our patient cohort by Cox regression analysis. However, when hTERT and O6-DNA methylguanine-methyltransferase (MGMT) were included together, we observed an interaction between these 2 factors. To further investigate this interaction, we performed pairwise comparison of the 4 patient subcohorts grouped by hTERT-MGMT status (MUT-M, WT-M, MUT-U, and WT-U). MGMT methylated patients showed improved survival only in the presence of hTERT promoter mutation: MUT-M versus MUT-U (overall survival of 28.3 vs 15.9 mos, log-rank P < .0001 and progression-free survival of 15.4 vs 7.86 mo, log-rank P < .0001). These results were confirmed by Cox analyses. Analogously, the cohort from TCGA demonstrated survival benefit of MGMT promoter methylation only in patients with high hTERT expression. In addition, hTERT mutation was negatively prognostic in our MGMT unmethylated patients, while the analogous association with high expression was not observed in the cohort from TCGA.ConclusionThe prognostic influence of MGMT promoter methylation depends on hTERT promoter mutation. This interaction warrants further mechanistic investigation.
| S-EPMC5464302 | biostudies-literature