Urinary Exosomal Long Noncoding RNA TERC as a Noninvasive Diagnostic and Prognostic Biomarker for Bladder Urothelial Carcinoma

Journal of Immunology Research, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 9

Published: Jan. 25, 2022

Purpose. Bladder cancer is one of the most common urological malignancies worldwide, and approximately 90% bladder cases are histologically typed as urothelial carcinoma (BLCA). Exosomes 30 to 200 nm extracellular vesicles that transport microRNAs, long noncoding RNAs (lncRNAs), mRNAs, circular RNAs, proteins across tissues through circulation. Urinary exosomes may contain genetic information from tumor cells. Herein, we explored clinical significance urinary exosomal lncRNA telomerase RNA component (TERC) levels provide an urgently needed diagnostic prognostic biomarker for BLCA. Materials Methods. In this study, used RNA-sequencing samples four BLCA patients three healthy controls identify TERC was differentially expressed in exosomes. We then quantitative PCR different types validate analyzed results using receiver operating characteristic curves. Results. found significantly upregulated compared with those ( $P<0.0001$ ). showed higher sensitivity (78.65%) accuracy (77.78%) than existing indicators including nuclear matrix protein-22 urine cytometry. Using cut-off value 4.302, area under curve 0.836 (95% confidence interval: 0.768–0.891, id="M2"> Furthermore, noninvasive assay could distinguish low-grade high-grade tumors id="M3"> = 0.0153 Conclusions. enriched patients. become a allows clinicians realize detection

Language: Английский

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TERT promoter mutations and methylation for telomerase activation in urothelial carcinomas: New mechanistic insights and clinical significance

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 12, 2023

Telomerase, an RNA-dependent DNA polymerase synthesizing telomeric TTAGGG sequences, is primarily silent in normal human urothelial cells (NHUCs), but widely activated cell-derived carcinomas or (UCs) including UC of the bladder (UCB) and upper track (UTUC). Telomerase activation for telomere maintenance required development progression, key underlying mechanism transcriptional de-repression telomerase reverse transcriptase (TERT), a gene encoding rate-limiting, catalytic component. Recent mechanistic explorations have revealed important roles TERT promoter mutations aberrant methylation transcription UCs. Moreover, these TERT-featured genomic epigenetic alterations been evaluated their usefulness non-invasive diagnostics, recurrence monitoring, outcome prediction response to treatments such as immunotherapy. Importantly, detection mutated mRNA urinary biomarkers holds great promise urine-based liquid biopsy. In present article, we review recent insights into altered promoter-mediated UCs discuss potential clinical implications. Specifically, compare differences senescence transformation between NHUCs other types epithelial cells, address interaction factors affect progression outcomes, evaluate impact TERT-mediated endogenous retrovirus genes on immunotherapy Bacillus Calmette-Guérin therapy immune checkpoint inhibitors. Finally, suggest standardization assay evaluation system practice.

Language: Английский

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Advancements in Urothelial Cancer Care: Optimizing Treatment for Your Patient

American Society of Clinical Oncology Educational Book, Journal Year: 2024, Volume and Issue: 44(3)

Published: May 21, 2024

The standard treatment paradigm for muscle invasive bladder cancer has been neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. However, efforts are ongoing to personalize incorporating biomarkers better guide selection. In addition, preservation strategies aimed at avoiding cystectomy in well-selected patients. Similarly, the metastatic urothelial space, frontline option of platinum-based changed with availability data from EV-302 trial, making combination enfortumab vedotin (EV) and pembrolizumab preferred first-line option. Here, we examine optimization intensity sequencing, focusing on challenges opportunities associated EV/pembrolizumab therapy, including managing toxicities exploring alternative dosing approaches. Together, these articles provide a comprehensive overview contemporary management, highlighting importance individualized approaches, research, multidisciplinary collaboration improve patient outcomes this complex disease landscape.

Language: Английский

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TERT Promoter Mutations as Simple and Non-Invasive Urinary Biomarkers for the Detection of Urothelial Bladder Cancer in a High-Risk Region

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(22), P. 14319 - 14319

Published: Nov. 18, 2022

Bladder cancer (BC) is the 10th most common in world. While there are FDA-approved urinary assays to detect BC, none have demonstrated sufficient sensitivity and specificity be integrated into clinical practice. Telomerase Reverse Transcriptase (TERT) gene mutations been identified as BC that could potentially used non-invasive biomarkers BC. This study aims evaluate validity of these tests Kerman province Iran, where men. Urine samples 31 patients with primary (n = 11) or recurrent 20) bladder tumor 50 controls were prospectively collected. Total DNA was screened for TERT promoter (uTERTpm) by Droplet Digital PCR (ddPCR) assays. The performance characteristics uTERTpm influence disease stage grade compared urine cytology results. 100% sensitive 88% specific while it 50% detecting overall 67.7% 88.0%, respectively, which consistent across different stages grades. frequent among cases C228T (18/31), C250T (4/31), C158A (1/31) mutant allelic frequency (MAF) ranging from 0.2% 63.3%. a similar (67.7%), but lower (62.0%) than Combined increased 83.8%, decreased 52.0%. Our promising diagnostic accuracy biomarker detect, particular, this population.

Language: Английский

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Characterization of novel mutations in the TEL-patch domain of the telomeric factor TPP1 associated with telomere biology disorders

Human Molecular Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 4, 2024

Abstract Telomeres are nucleoprotein structures that protect the chromosome ends from degradation and fusion. Telomerase is a ribonucleoprotein complex essential to maintain length of telomeres. Germline defects lead short and/or dysfunctional telomeres cause telomere biology disorders (TBDs), group rare heterogeneous Mendelian diseases including pulmonary fibrosis, dyskeratosis congenita, Høyeraal-Hreidarsson syndrome. TPP1, telomeric factor encoded by gene ACD, recruits telomerase at stimulates its activity via TEL-patch domain directly interacts with TERT, catalytic subunit telomerase. TBDs due TPP1 deficiency have been reported only in 11 individuals. We here report four unrelated individuals wide spectrum TBD manifestations carrying either heterozygous or homozygous ACD variants consisting recurrent previously described in-frame deletion K170 (K170∆) three novel missense mutations G179D, L184R, E215V. Structural functional analyses demonstrated affect impair activity. In addition, we identified several motifs associated small hotspots could explain recurrence K170∆ mutation. Finally, detected subset blood cells one patient, somatic TERT promoter-activating mutation likely provides selective advantage over non-modified cells, phenomenon known as indirect genetic rescue. Together, our results broaden clinical specify new residues crucial for maintenance stability human vivo.

Language: Английский

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Evaluation of Somatic Mutations in Urine Samples as a Noninvasive Method for the Detection and Molecular Classification of Endometrial Cancer

Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 29(18), P. 3681 - 3690

Published: July 13, 2023

Current diagnostic methods for endometrial cancer lack specificity, leading to many women undergoing invasive procedures. The aim of this study was evaluate somatic mutations in urine accurately discriminate patients with from controls.Overall, 72 samples were analyzed using next-generation sequencing (NGS) molecular identifiers targeting 47 genes. We evaluated supernatant (n = 19) and age-matched controls 20). Cell pellets plasma seven cases sequenced; further, we also paired tumor all cases. Finally, immunohistochemical markers profiling samples.Overall, able identify DNA 100% cancers. In contrast, only one control (5%) showed variants at a variant allele frequency (VAF) ≥ 2% the samples. classification obtained by good agreement. Analyses revealed higher number VAF supernatants than cell blood samples.Evaluation may offer user-friendly reliable tool detection classification. performance very high, could be molecularly classified these noninvasive self-collected Additional multicenter evaluations larger sample sizes are needed validate results understand potential early prognosis cancer.

Language: Английский

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Regulatory region mutations of TERT, PLEKHS1 and GPR126 genes as urinary biomarkers in upper tract urothelial carcinomas

Journal of Cancer, Journal Year: 2021, Volume and Issue: 12(13), P. 3853 - 3861

Published: Jan. 1, 2021

Background:The hotspot regulatory region mutations of the TERT, PLEKHS1 and GPR126 genes have been shown to occur frequently in urothelial bladder carcinoma (UBC).However, it is currently unclear whether these are all present upper tract carcinomas (UTUC) including renal pelvic (RPC) ureter (UC), although TERT promoter were previously observed malignancies.Methods: The promoters intron 6 (enhancer) tumors derived from 164 patients with UTUC determined using Sanger sequencing, obtained results further compared mutation frequency 106 UBCs.The also assessed urine UBC.Results: frequencies 28%, 5.8% 11% for 6, respectively, which lower than those (44.3%,26.4%, 31.4%,respectively) total presence any 50.8% 34.4% RPCs UCs, respectively.All mutated DNA sequences detectable both UBC disappeared rapidly most after surgery.Conclusions: This proof-of-concept study demonstrates that non-coding regions UTUCs, urinary assays serve as potential biomarkers diagnostics disease monitoring.

Language: Английский

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Application of Droplet Digital PCR Technology in Muscular Dystrophies Research

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(9), P. 4802 - 4802

Published: April 27, 2022

Although they are considered rare disorders, muscular dystrophies have a strong impact on people’s health. Increased disease severity with age, frequently accompanied by the loss of ability to walk in some people, and lack treatment, directed researchers towards development more effective therapeutic strategies aimed improve quality life expectancy, slow down progression, delay onset or convert severe phenotype into milder one. Improved understanding complex pathology these diseases together tremendous advances molecular biology technologies has led personalized procedures. Different approaches that currently under extensive investigation require efficient, sensitive, less invasive methods. Due its remarkable analytical sensitivity, droplet digital PCR become promising tool for accurate measurement biomarkers monitor progression quantification various efficiency can be non-invasive prenatal diagnosis newborn screening. Here, we summarize recent applications dystrophy research discuss factors should get best performance this technology.

Language: Английский

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Clinical Utility of Plasma KRAS, NRAS and BRAF Mutational Analysis with Real Time PCR in Metastatic Colorectal Cancer Patients—The Importance of Tissue/Plasma Discordant Cases

Journal of Clinical Medicine, Journal Year: 2020, Volume and Issue: 10(1), P. 87 - 87

Published: Dec. 29, 2020

Background: Tumor tissue (T) mutational analysis represents the standard for metastatic colorectal cancer (mCRC); however, circulating tumor DNA (ctDNA) detected by liquid biopsy in plasma (PL) can better represent heterogeneity. Methods: mCRC patients undergoing first-line chemotherapy with known T-KRAS/NRAS/BRAF status were enrolled present prospective study. PL mutations assessed within 2 weeks before start real time PCR and correlated T Progression free survival (PFS). Clinical biochemical variables including also total number of lesions (TNL) sum maximum diameter (SMD) all as potential predictors T/PL discordance. RESULTS: Among 45 patients, BRAF concordant between there 20% RAS discordant: 9% wild type mutated 11% PL. significantly associated to median PFS (mPFS 4.5, 8.3 22.9 months T-BRAF mutated, T-RAS T-wild respectively, p trend 0.00014). further refined prognosis: had shorter than PL: mPFS 9.6 vs. 23.3 months, = 0.02. Patients longer 24.4 7.8 0.008. At a multivariate cox regression PFS, independent prognostic factor superior (HR 0.13, 0.0008). logistic TNL SMD significant discordant cases. Conclusions: allows prognostication alone could help treatment management.

Language: Английский

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Urine TERT promoter mutations‑based tumor DNA detection in patients with bladder cancer: A pilot study

Molecular and Clinical Oncology, Journal Year: 2021, Volume and Issue: 15(6)

Published: Oct. 8, 2021

Telomerase reverse transcriptase (TERT) promoter mutations are the most frequent genetic events in bladder cancer (BC). The aim of present pilot study was to evaluate diagnostic potential urine TERT mutations-based liquid biopsy patients with an ongoing oncological process, as well post-resection at risk BC recurrence. A total 60 were enrolled, whom 27 had histologically proven BC; 23 no signs (control group); and 10 underwent transurethral malignancy resection 3-6 months prior donation ('second look' group). Urine detected using Droplet Digital PCR. Receiver operating characteristic curve analysis revealed significant power approach (area under curve: -0.768). At cut-off value tumor DNA fraction 0.34%, sensitivity specificity 55.56 100%, respectively. In positive samples, varied significantly from 0.59 48.77%. 'second group, 4/10 patients, highlighting possibility recurrence its ranging only 0.90 6.61%. Therefore, appears be a promising tool for diagnosis surveillance. main will include recruitment additional extension mutation panel, prolonged follow-up screening industrial workers exposed specific carcinogens.

Language: Английский

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