tRNA-Derived Fragments (tRFs) in Bladder Cancer: Increased 5′-tRF-LysCTT Results in Disease Early Progression and Patients’ Poor Treatment Outcome

Cancers, Journal Year: 2020, Volume and Issue: 12(12), P. 3661 - 3661

Published: Dec. 6, 2020

The heterogeneity of bladder cancer (BlCa) prognosis and treatment outcome requires the elucidation tumors’ molecular background towards personalized patients’ management. tRNA-derived fragments (tRFs), although originally considered as degradation debris, represent a novel class powerful regulatory non-coding RNAs. In silico analysis TCGA-BLCA project highlighted 5′-tRF-LysCTT to be significantly deregulated in tumors, levels were further quantified our screening cohort 230 BlCa patients. Recurrence progression for non-muscle invasive (NMIBC) patients, well patient’s death muscle-invasive (MIBC) used clinical endpoint events. validation cohort. Bootstrap was performed internal net benefit on disease assessed by decision curve analysis. Elevated associated with unfavorable features, significant higher risk early (multivariate Cox: HR = 2.368; p 0.033) poor survival 2.151; 0.032) NMIBC MIBC respectively. Multivariate models integrating established markers resulted superior risk-stratification specificity positive prediction progression. conclusion, increased strongly adverse improved prognostication.

Language: Английский

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Development of Sensitive Droplet Digital PCR Assays for Detecting Urinary TERT Promoter Mutations as Non-Invasive Biomarkers for Detection of Urothelial Cancer

Cancers, Journal Year: 2020, Volume and Issue: 12(12), P. 3541 - 3541

Published: Nov. 27, 2020

Somatic mutations in the telomerase reverse transcriptase (TERT) promoter regions are frequent events urothelial cancer (UC) and their detection urine (supernatant cell-free DNA or from exfoliated cells) could serve as putative non-invasive biomarkers for UC monitoring. However, detecting these tumor-borne requires highly sensitive methods, capable of measuring low-level mutations. In this study, we developed droplet digital PCR (ddPCR) assays TERT (C228T, C228A, CC242-243TT, C250T). We tested C228T C250T ddPCR on all samples with sufficient quantity urinary (urine supernatant (US cfDNA) pellet cellular (UP cellDNA)) DIAGURO (n = 89/93 cases n 92/94 controls) IPO-PORTO 49/50 50/50 series that were previously screened UroMuTERT assay compared performance two approaches. series, sensitivity specificity using either US cfDNA UP cellDNA 86.8% 92.4%. The was slightly higher than (67.4% vs. 65.3%, respectively), but not (86.8% 90.7%). 100% controls both assays, whereas dropped (92.4% versus 95.6%). Overall, an almost perfect agreement between methods observed 164; kappa coefficient 0.91) 280; 0.94). a large independent serial follow-up BC 394), (i) strong (kappa 0.87), regardless types 0.89 0.85 cellDNA), (ii) highest mutant allelic fractions (MAFs) > 2% 0.99) (iii) only minimal lowest MAFs (< 0.5%; 0.32). Altogether, our results indicate (ddPCR UroMuTERT) comparable discrepancies relate to low-allelic fraction simplicity makes them suitable implementation clinical settings.

Language: Английский

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Non-Muscle Invasive Bladder Cancer with Variant Histology: Biological Features and Clinical Implications

Oncology, Journal Year: 2021, Volume and Issue: 99(6), P. 345 - 358

Published: Jan. 1, 2021

<b><i>Background:</i></b> The most common bladder cancer (BC) histotype is pure urothelial carcinoma (UC), which may undergo divergent differentiation in some cases. Variant histology (VH) presents along variable morphologies, either single or combined between them with UC. From a clinical standpoint, the vast majority of BC diagnosed at non-invasive minimally invasive stages, namely as non-muscle (NMIBC). There wide range therapeutic options for patients NMIBC, according to their and pathological features. However, current risk stratification models do not show optimal effectiveness. Evidence from literature suggests that VH has peculiar biological features, be associated poorer survival outcomes compared <b><i>Summary:</i></b> In order describe features prognostic/predictive role discuss treatment options, we performed systematic search through multiple databases (PubMed/Medline, Google Scholar) relevant articles following terms, and/or combination: “non-muscle cancer,” “variant histology,” “micropapillary variant,” “glandular differentiation,” “squamous “nested “plasmacytoid “sarcomatoid variant.” We extracted 99 studies including original articles, reviews, subsequently analyzed data 16 reporting on outcome NMIBC VH. found relative rarity these forms well heterogeneity study populations protocols results conflicting findings overall. <b><i>Key Messages:</i></b> presence should taken into account when counseling patient since it upgrade disease high-risk tumor thus warrant more aggressive treatment.

Language: Английский

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Molecular Classification of Bladder Urothelial Carcinoma Using NanoString-Based Gene Expression Analysis

Cancers, Journal Year: 2021, Volume and Issue: 13(21), P. 5500 - 5500

Published: Nov. 1, 2021

Molecular classification of bladder carcinoma is a relevant topic in modern cancer oncology due to its potential improve oncological outcomes. The available molecular classifications are generally based on transcriptomic profiles, generating highly diverse categories with limited correlation. Implementation practice typically the high complexity required technology, elevated costs, and availability this technology worldwide. We have conducted gene expression analysis using four-gene panel related luminal basal subtypes series 91 cases. NanoString-based (GATA3+/KRT20+) markers (KRT14+/KRT5+/GATA3low/-/KRT20low/-) classified urothelial samples as luminal, basal, third category (KRT14-/KRT5-/GATA3-/KRT20-), null/double negative (non-luminal/non-basal). These three were meaningful terms overall cancer-specific survival (p < 0.0001) or when conventional variant histology 0.0001), NMIBC vs. MIBC 0.001), by AJCC stage Ta = 0.0012) T1 but did not reach significance T2-T4 0.563). PD-L1 (low high) was also different according subtype, mostly seen null carcinomas 0.002). Additionally, subtype enriched favorable 0.0001). In contrast, resulted aggressive tumors shorter some which presented histology. conclusion, comprehensive evaluation classifier taxonomy NanoString feasible. Therefore, it might represent an accessible affordable tool rapidly expanding area precision genomics.

Language: Английский

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Molecular Oncology of Bladder Cancer from Inception to Modern Perspective

Cancers, Journal Year: 2022, Volume and Issue: 14(11), P. 2578 - 2578

Published: May 24, 2022

Within the last forty years, seminal contributions have been made in areas of bladder cancer (BC) biology, driver genes, molecular profiling, biomarkers, and therapeutic targets for improving personalized patient care. This overview includes discoveries advances oncology BC. Starting with concept divergent pathways development low- high-grade tumors, field cancerization versus clonality genes/mutations, genetic polymorphisms, bacillus Calmette-Guérin (BCG) as an early form immunotherapy are some conceptual towards Although beginning a promise predicting prognosis individualizing treatments, "-omic" approaches subtypes revealed importance BC stem cells, lineage plasticity, intra-tumor heterogeneity next frontiers realizing individualized Along urine optimal non-invasive liquid biopsy, is at forefront biomarker field. If goal to reduce number cystoscopies but not replace them monitoring recurrence asymptomatic microscopic hematuria, marker may reach clinical acceptance. As continue, twenty-five years should significantly advance care patients.

Language: Английский

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