Comment on "telomerase reverse transcriptase rs2736098 and rs2736100 in bladder cancer".
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ABSTRACT:
SUBMITTER: Mungmunpuntipantip R
PROVIDER: S-EPMC10132187 | biostudies-literature | 2023
REPOSITORIES: biostudies-literature
Publications
Comment on "telomerase reverse transcriptase rs2736098 and rs2736100 in bladder cancer".
Mungmunpuntipantip Rujittika R Wiwanitkit Viroj V
Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology 20230406 1
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Project description:BackgroundA meta-analysis was conducted to determine whether telomerase reverse transcriptase (TERT) rs2736098 polymorphism was related to the incidence of lung cancer.MethodsWe systematically searched the following three electronic databases: PubMed, Embase, and China National Knowledge Infrastructure (CNKI), for relevant articles. Statistical analysis was performed using the odds ratio (OR) and the corresponding 95% confidence interval (CI).ResultsSeven articles involving 3836 healthy controls and 3637 patients were included in this meta-analysis. TERT rs2736098 polymorphism was significantly related to lung cancer incidence (AA vs. GG: OR=1.83, 95% CI=1.58-2.12; AG vs. GG: OR=1.21, 95% CI=1.10-1.34; Dominant model: OR=1.33, 95% CI=1.22-1.46; Recessive model: OR=1.66, 95% CI=1.44-1.90). Moreover, this polymorphism was found to be correlated with the susceptibility to lung cancer when studies were stratified based on the sample size and the Hardy-Weinberg equilibrium.ConclusionThe present findings indicate that the TERT rs2736098 polymorphism may be a risk factor for the development of lung cancer.
| S-EPMC7555572 | biostudies-literature
Project description:The enzyme telomerase reverse transcriptase (TERT) is essential for telomere maintenance. In replicating cells, maintenance of telomere length is important for the preservation of vital genetic information and prevention of genomic instability. A common genetic variant in TERT, rs2736100 C/A, is associated with both telomere length and multiple diseases. Carriage of the C allele is associated with longer telomere length, while carriage of the A allele is associated with shorter telomere length. Furthermore, some diseases have a positive association with the C and some with the A allele. In this study, meta-analyses were performed for two groups of diseases, cancerous diseases, e.g., lung cancer and non-cancerous diseases, e.g., pulmonary fibrosis, using data from genome-wide association studies and case-control studies. In the meta-analysis it was found that cancer positively associated with the C allele (pooled OR 1.16 [95% CI 1.09-1.23]) and non-cancerous diseases negatively associated with the C allele (pooled OR 0.81 [95% CI 0.65-0.99]). This observation illustrates that the ambiguous role of telomere maintenance in disease hinges, at least in part, on a single locus in telomerase genes. The dual role of this single nucleotide polymorphism also emphasizes that therapeutic agents aimed at influencing telomere maintenance should be used with caution.
| S-EPMC5835035 | biostudies-literature
Project description:Genetic variants from a considerable number of susceptibility loci have been identified in association with cancer risk, but their interaction with epidemiologic factors in lung cancer remains to be defined. We sought to establish a forecasting model for identifying individuals with high-risk of lung cancer by combing gene single-nucleotide polymorphisms with epidemiologic factors. Genotyping and clinical data from 500 lung cancer cases and 500 controls were used for developing the logistic regression model. We found that lung cancer was associated with telomerase reverse transcriptase (TERT) rs2736100 single-nucleotide polymorphism. The TERT rs2736100 model was still significantly associated with lung cancer risk when combined with environmental and lifestyle factors, including lower education, lower BMI, COPD history, heavy cigarettes smoking, heavy cooking emission, and dietary factors (over-consumption of meat and deficiency in fish/shrimp, vegetables, dairy products, and soybean products). These data suggest that combining TERT SNP and epidemiologic factors may be a useful approach to discriminate high and low-risk individuals for lung cancer.
| S-EPMC4860802 | biostudies-literature
Project description:The rs2736100 polymorphism in telomerase reverse transcriptase (TERT) gene has been implicated as a risk factor for glioma in previous epidemiological studies. However, the data from these studies were inconclusive for the precise association of TERT rs2736100 with glioma. Here we employed a meta-analysis aiming to evaluate such association. The PubMed, Embase, and Web of Science were systematically searched for eligible studies. The odds ratio (OR) and 95% confidence interval (95% CI) was estimated to assess the strength of this association in fixed or random effects models. A total of 5 studies in 16 articles including 7337 cases and 12062 controls were eventually collected. Our analyses showed that there was a significant association between TERT rs2736100 polymorphism and glioma in all five genetic models(homozygous model-GG vs. TT: OR=1.64, 95% CI=1.50~1.79, P heterogeneity=0.253, I(2) =17.5%; heterozygous model-GT vs. TT: OR=1.38, 95% CI=1.27~1.49, P heterogeneity=0.235, I(2) =19.1%; dominant model-GG+GT vs. TT: OR=1.46, 95% CI=1.36~1.57, P heterogeneity=0.167, I(2) =25.5%; recessive model-GG vs. GT+TT: OR=1.31, 95% CI=1.22~1.40, P heterogeneity=0.796, I(2) =0.0%; additive model-G allele vs. T allele: OR=1.27, 95% CI=1.21~1.32, P heterogeneity=0.481, I(2) =0.0%). Further subgroup analysis on control source and ethnicity, we found similar association in population-based, hospital-based and Caucasians groups. The result of heterogeneity test were in acceptable range (P<0.05 and I(2) <50%). Egger's tests and Begg's funnel plot did not show any publication bias. Sensitivity analysis confirmed that our results were reliable. Taken together, our meta-analysis suggested that TERT rs2736100 polymorphism may greatly increase glioma risk.
| S-EPMC4358468 | biostudies-literature
Project description:Telomerase reverse transcriptase (TERT) promoter mutations have been recognized as a common genetic event in bladder cancer (BC). Many studies have found the high TERT promoter mutations' prevalence in BC recurrence patients which may make the TERT promoter mutations become a potential prognosis prediction of BC. We performed a systematic search in Embase, PubMed, and Web of Science in January 2021. The aspects of evaluation, methods, validation, and results were used to evaluate the included studies' quality. We reviewed two of the most common mutations in types of TC, C288T and C250T and their relationship with prognosis of BC. Eight studies contained 1382 cases were enrolled in our study. The percentage of TERT promoter mutations in these cases was 62.5%. A statistically significant association was detected between TERT promoter mutation and recurrence (HR: 2.03, 95% CI: 1.53-2.68, p < 0.001). However, TERT promoter mutation was not significant associated with overall survival (HR: 1.077, 95% CI: 0.674-1.718, p = 0.757). No significant heterogeneities were observed (I2 = 47.5%, P = 0.064; I2 = 58.7%, p = 0.120, respectively). Bladder cancer patients with TERT promoter mutations take a higher risk of recurrence. TERT promoter mutations may become a potential prediction factor for bladder cancer recurrence.
| S-EPMC8806350 | biostudies-literature
Project description:Telomeres, the repetitive sequences at chromosomal ends, protect intact chromosomes. Telomeres progressively shorten through successive rounds of cell divisions, and critically shortened telomeres trigger senescence and apoptosis. The enzyme that elongates telomeres and maintains their structure is known as telomerase. The catalytic subunit of this enzyme (telomerase reverse transcriptase [TERT]) is expressed at a high level in malignant cells, but at a very low level in normal cells. Although telomerase activity was long believed to be the only function of TERT, emerging evidence indicates that TERT plays roles beyond telomeres. For example, TERT contributes to stem cell maintenance and cell reprogramming processes in a manner independent of its canonical function. Even some types of splice variants that lack the telomerase catalytic domains exhibit the functions in a manner that does not depend on telomerase activity. We recently demonstrated that the RNA-dependent RNA polymerase (RdRP) activity of TERT is involved in regulation of gene silencing and heterochromatic transcription. Moreover, TERT RdRP activity is mediated by a newly identified complex, distinct from the authentic telomerase complex, that plays a role in cancer stem cells in a telomere maintenance independent manner. TERT has attracted interest as a molecular target for anticancer treatment, but previous efforts aimed at developing novel therapeutic strategies focused only on the canonical function of TERT. However, accumulating evidence about the non-canonical functions of TERT led us to speculate that the functions other than telomerase might be therapeutic targets as well. In this review, we discuss the non-canonical functions of TERT and their potential applications for anticancer treatment.
| S-EPMC4714691 | biostudies-literature
Project description:BackgroundA common genetic variant, telomerase reverse transcriptase (TERT) rs2736098, was recently reported to be associated with lung cancer risk in Caucasians. In addition, many studies have investigated the role of this polymorphism in the etiology of cancer of various organs. Nevertheless, the results of related case-control studies remain inconsistent.MethodsWe hypothesized that the genetic risk variant identified in Caucasians may potentially influence the susceptibility to lung cancer in the Chinese population. To test this hypothesis, a case-control study including 539 non-small-cell lung cancer (NSCLC) cases and 627 cancer-free controls was conducted. Furthermore, to investigate the association between rs2736098 and cancer risk, a meta-analysis based on previously published studies and our case-control study was also performed.ResultsMultivariate logistic regression demonstrated that individuals carrying the A allele or the AA genotype exhibited a significantly elevated risk of NSCLC compared with those carrying the G allele or GG genotype (A vs. G: OR = 1.21, 95% CI = 1.02-1.43, P = 0.028; AA vs. GG: OR = 1.48, 95% CI = 1.05-2.09, P = 0.025). Additionally, this association was stronger among adenocarcinoma cases (AA vs. GG: OR = 1.67, 95% CI = 1.12-2.50, P = 0.013; A vs. G: OR = 1.28, 95% CI = 1.05-1.57, P = 0.016). In the meta-analysis, a borderline significant association between the rs2736098 polymorphism and overall cancer risk was observed (AA vs. GG: OR = 1.25, 95% CI = 1.07-1.46; AA vs. AG+GG: OR = 1.22, 95% CI = 1.06-1.41; additive model: OR = 1.10, 95% CI = 1.02-1.18), and further stratifications demonstrated a moderately increased risk for lung and bladder cancer, Asian ethnicity and hospital-based studies.ConclusionsOur results suggest that the rs2736098 polymorphism may contribute to the risk of lung cancer, especially adenocarcinoma, in the Chinese population. In addition, the current meta-analysis indicates that this genetic variant is only weakly associated with overall cancer risk. However, the rs2736098 polymorphism may affect individual susceptibility to lung and bladder cancer. Further studies are needed to validate our findings.
| S-EPMC3834105 | biostudies-literature
Project description:A single nucleotide polymorphism (SNP) in the second intron of human TERT (hTERT), rs2736100, acts as a critical factor in hTERT synthesis and activation. The rs2736100 SNP was found to be associated with susceptibility to many cancers. Recently, inhibition of telomerase and marked telomere shortening were determined to be closely associated with the increasing severity of atherosclerosis. The association between the SNP of rs2736100 and the presence of atherosclerosis was evaluated in 84 atherosclerosis patients and 257 healthy controls using multivariate logistic regression analyses. The proportion of the GG genotype in atherosclerosis patients (17.9%) was significantly higher than in the control group (9.7%). Eight variables, including age, gender, cholesterol, high density lipoprotein, homocysteine, total bilirubin, indirect bilirubin, and rs2736100 GG genotype, were associated with atherosclerosis with odds ratios of 1.88, 2.11, 1.66, 0.23, 1.27, 1.29, 1.53, and 1.74, respectively, using multivariate logistic regression analyses. Homozygous GG was demonstrated to be associated with the presence of atherosclerosis in our population.
| S-EPMC3897494 | biostudies-literature
Project description:The Hedgehog (HH) signaling pathway is critical for normal embryonic development, tissue patterning and cell differentiation. Aberrant HH signaling is involved in multiple human cancers. HH signaling involves a multi-protein cascade activating the GLI proteins that transcriptionally regulate HH target genes. We have previously reported that HH signaling is essential for human colon cancer cell survival and inhibition of this signal induces DNA damage and extensive cell death. Here we report that the HH/GLI axis regulates human telomerase reverse transcriptase (hTERT), which determines the replication potential of cancer cells. Suppression of GLI1/GLI2 functions by a C-terminus truncated GLI3 repressor mutant (GLI3R), or by GANT61, a pharmacological inhibitor of GLI1/GLI2, reduced hTERT protein expression in human colon cancer, prostate cancer and Glioblastoma multiforme (GBM) cell lines. Expression of an N-terminus deleted constitutively active mutant of GLI2 (GLI2ΔN) increased hTERT mRNA and protein expression and hTERT promoter driven luciferase activity in human colon cancer cells while GANT61 inhibited hTERT mRNA expression and hTERT promoter driven luciferase activity. Chromatin immunoprecipitation with GLI1 or GLI2 antibodies precipitated fragments of the hTERT promoter in human colon cancer cells, which was reduced upon exposure to GANT61. In contrast, expression of GLI1 or GLI2ΔN in non-malignant 293T cells failed to alter the levels of hTERT mRNA and protein, or hTERT promoter driven luciferase activity. Further, expression of GLI2ΔN increased the telomerase enzyme activity, which was reduced by GANT61 administration in human colon cancer, prostate cancer, and GBM cells. These results identify hTERT as a direct target of the HH signaling pathway, and reveal a previously unknown role of the HH/GLI axis in regulating the replication potential of cancer cells. These findings are of significance in understanding the important regulatory mechanisms that determine the functions of HH/GLI signaling in cancer cells.
| S-EPMC3783395 | biostudies-literature
Project description:Telomerase maintains the simple sequence repeats at chromosome ends, protecting cells from genomic rearrangement, proliferative senescence and death. The telomerase reverse transcriptase (TERT) and telomerase RNA (TER) alone can assemble into active enzyme in a heterologous cell extract, but the physiological process of telomerase biogenesis is more complex. The endogenous accumulation of Tetrahymena thermophila TERT and TER requires an additional telomerase holoenzyme protein, p65. Here, we reconstitute this cellular pathway for telomerase ribonucleoprotein biogenesis in vitro. We demonstrate that tandem RNA interaction domains in p65 recognize the sequence of the TER 3' stem. Notably, the p65-TER complex recruits TERT much more efficiently than does TER alone. Using bacterially expressed p65 and TERT polypeptides, we show that p65 enhances TERT-TER interaction by a mechanism involving a conserved bulge in the protein-bridging TER molecule. These findings reveal a pathway for telomerase holoenzyme biogenesis that preassembles TER for TERT recruitment.
| S-EPMC2913471 | biostudies-literature