NTRK3 exhibits a pro-oncogenic function in upper tract urothelial carcinomas.

Neurotrophic receptor tyrosine kinase 3 (NTRK3) has pleiotropic functions: it acts not only as an oncogene in breast and gastric cancers but also as a dependence receptor in tumor suppressor genes in colon cancer and neuroblastomas. However, the role of NTRK3 in upper tract urothelial carcinoma (UTUC) is not well documented. This study investigated the association between NTRK3 expression and outcomes in UTUC patients and validated the results in tests on UTUC cell lines. A total of 118 UTUC cancer tissue samples were examined to evaluate the expression of NTRK3. Survival curves were generated using Kaplan-Meier estimates, and Cox regression models were used for investigating survival outcomes. Higher NTRK3 expression was correlated with worse progression-free survival, cancer-specific survival, and overall survival. Moreover, the results of an Ingenuity Pathway Analysis suggested that NTRK3 may interact with the PI3K-AKT-mTOR signaling pathway to promote cancer. NTRK3 downregulation in BFTC909 cells through shRNA reduced cellular migration, invasion, and activity in the AKT-mTOR pathway. Furthermore, the overexpression of NTRK3 in UM-UC-14 cells promoted AKT-mTOR pathway activity, cellular migration, and cell invasion. From these observations, we concluded that NTRK3 may contribute to aggressive behaviors in UTUC by facilitating cell migration and invasion through its interaction with the AKT-mTOR pathway and the expression of NTRK3 is a potential predictor of clinical outcomes in cases of UTUC.

Genomic Profiling and Molecular Characterisation of Metastatic Urothelial Carcinoma.

The clinical management of metastatic urothelial carcinoma (mUC) is undergoing a major paradigm shift; the integration of immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) into the mUC therapeutic strategy has succeeded in improving platinum-based chemotherapy outcomes. Given the expanding therapeutic armamentarium, it is crucial to identify efficacy-predictive biomarkers that can guide an individual patient's therapeutic strategy. We reviewed the literature data on mUC genomic alterations of clinical interest, discussing their prognostic and predictive role. In particular, we explored the role of the fibroblast growth factor receptor (FGFR) family, epidermal growth factor receptor 2 (HER2), mechanistic target of rapamycin (mTOR) axis, DNA repair genes, and microsatellite instability. Currently, based on the available clinical data, FGFR inhibitors and HER2-directed ADCs are effective therapeutic options for later lines of biomarker-driven mUC. However, emerging genomic data highlight the opportunity for earlier use and/or combination with other drugs of both FGFR inhibitors and HER2-directed ADCs and also reveal additional potential drug targets that could change mUC management.

Beyond the genome: MALAT1's role in advancing urologic cancer care.

Urologic cancers (UCs), which include bladder, kidney, and prostate tumors, account for almost a quarter of all malignancies. Long non-coding RNAs (lncRNAs) are tissue-specific RNAs that influence cell growth, death, and division. LncRNAs are dysregulated in UCs, and their abnormal expression may allow them to be used in cancer detection, outlook, and therapy. With the identification of several novel lncRNAs and significant exploration of their functions in various illnesses, particularly cancer, the study of lncRNAs has evolved into a new obsession. MALAT1 is a flexible tumor regulator implicated in an array of biological activities and disorders, resulting in an important research issue. MALAT1 appears as a hotspot, having been linked to the dysregulation of cell communication, and is intimately linked to cancer genesis, advancement, and response to treatment. MALAT1 additionally operates as a competitive endogenous RNA, binding to microRNAs and resuming downstream mRNA transcription and operation. This regulatory system influences cell growth, apoptosis, motility, penetration, and cell cycle pausing. MALAT1's evaluation and prognosis significance are highlighted, with a thorough review of its manifestation levels in several UC situations and its association with clinicopathological markers. The investigation highlights MALAT1's adaptability as a possible treatment target, providing fresh ways for therapy in UCs as we integrate existing information The article not only gathers current knowledge on MALAT1's activities but also lays the groundwork for revolutionary advances in the treatment of UCs.

SGLT2 inhibition and three urological cancers: Up-to-date results.

OBJECTIVE: To identify the causal role of sodium-glucose cotransporter 2 (SGLT2) inhibition on three urological cancers. METHODS: Six single nucleotide polymorphisms associated with the expression level of SLC5A2, a proxy for SGLT2 inhibition, from a recent publication were extracted. Three common urological cancers, including bladder cancer, prostate cancer and kidney cancer, were analysed. The main cohort of bladder cancer was derived from UK Biobank (1279 cases and 372,016 controls). The prostate cancer cohort was from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium (79,148 cases and 61,106 controls). The kidney cancer phenotype was from the UK Biobank cohort of 463,010 individuals (1114 cases and 461,896 controls). Primary and sensitivity analysis were performed to validate the results. In vitro analysis was also incorporated to validate the Mendelian randomisation results. RESULTS: In primary analysis, SGLT2 inhibition was associated with reduced risk of bladder cancer (OR: 0.98, 95% CI: 0.97-0.99) per unit lowering of HbA1c level. A protective association was also observed for prostate cancer with odds ratio = 0.31 (95% CI = 0.21-0.47). However, we did not discover a causal relationship between SGLT2 inhibition and kidney cancer (OR: 1.00, 95% CI: 0.99-1.00). Sensitivity analysis and in vitro validation did not support the causal role of SGLT2 inhibition in increasing cancer risk. CONCLUSIONS: We did not find any evidence that SGLT2 inhibition could increase the risk of the three cancers. Even in some analysis, SGLT2 inhibition tended to show protective effects on the three urological cancers.

A deep-learning workflow to predict upper tract urothelial carcinoma protein-based subtypes from H&E slides supporting the prioritization of patients for molecular testing.

Upper tract urothelial carcinoma (UTUC) is a rare and aggressive, yet understudied, urothelial carcinoma (UC). The more frequent UC of the bladder comprises several molecular subtypes, associated with different targeted therapies and overlapping with protein-based subtypes. However, if and how these findings extend to UTUC remains unclear. Artificial intelligence-based approaches could help elucidate UTUC's biology and extend access to targeted treatments to a wider patient audience. Here, UTUC protein-based subtypes were identified, and a deep-learning (DL) workflow was developed to predict them directly from routine histopathological H&E slides. Protein-based subtypes in a retrospective cohort of 163 invasive tumors were assigned by hierarchical clustering of the immunohistochemical expression of three luminal (FOXA1, GATA3, and CK20) and three basal (CD44, CK5, and CK14) markers. Cluster analysis identified distinctive luminal (N = 80) and basal (N = 42) subtypes. The luminal subtype mostly included pushing, papillary tumors, whereas the basal subtype diffusely infiltrating, non-papillary tumors. DL model building relied on a transfer-learning approach by fine-tuning a pre-trained ResNet50. Classification performance was measured via three-fold repeated cross-validation. A mean area under the receiver operating characteristic curve of 0.83 (95% CI: 0.67-0.99), 0.8 (95% CI: 0.62-0.99), and 0.81 (95% CI: 0.65-0.96) was reached in the three repetitions. High-confidence DL-based predicted subtypes showed significant associations (p < 0.001) with morphological features, i.e. tumor type, histological subtypes, and infiltration type. Furthermore, a significant association was found with programmed cell death ligand 1 (PD-L1) combined positive score (p < 0.001) and FGFR3 mutational status (p = 0.002), with high-confidence basal predictions containing a higher proportion of PD-L1 positive samples and high-confidence luminal predictions a higher proportion of FGFR3-mutated samples. Testing of the DL model on an independent cohort highlighted the importance to accommodate histological subtypes. Taken together, our DL workflow can predict protein-based UTUC subtypes, associated with the presence of targetable alterations, directly from H&E slides.

The role of miR-155 in urologic malignancies.

MicroRNAs (miRNAs) are a class of short non-coding RNAs that play a crucial role in regulating gene expression across multiple levels. They are involved in a wide range of physiological processes, including proliferation, differentiation, apoptosis, and cell cycle control. In recent years, miRNAs have emerged as pivotal regulatory molecules in the development and progression of tumors. Among these, miR-155 has garnered significant attention due to its high expression in various diseases, particularly urologic malignancies. Since an extensive corpus of studies having focused on the roles of miR-155 in various urologic malignancies, it is essential to summarize the current evidence on this topic through a comprehensive review. Altered miR-155 expression is related to various physiological and pathological processes, including immune response, inflammation, tumor development and treatment resistance. Notably, alterations in miR-155 expression have been observed in urologic malignancies as well. The up-regulation of miR-155 expression is commonly observed in urologic malignancies, contributing to their progression by targeting specific proteins and signaling pathways. This article provides a comprehensive review of the significant role played by miR-155 in the development of urologic malignancies. Furthermore, the potential of miR-155 as a biomarker and therapeutic target in urologic malignancies is also discussed.

Association of TIMP2 418 G/C and MMP Gene Polymorphism with Risk of Urinary Cancers: Systematic Review and Meta-analysis.

Aim: The matrix metalloproteinases (MMPs) inhibit tissue inhibitors of metalloproteinases (TIMPs), playing a notable role in various biological processes, and mutations in TIMP2 genes impact a variety of urinary cancers. In this study, we analyze and evaluate the potential involvement of the TIMP2 418 G/C and MMP gene polymorphism in the etiology of urinary cancer. Methodology: For suitable case-control studies, a literature search was undertaken from various database sources such as PubMed, EMBASE, and Google Scholar. Incorporated into the analysis were case-control or cohort studies that documented the correlation between TIMP2 418 G/C and urological cancers. MetaGenyo served as the tool for conducting the meta-analysis, employing a fixed-effects model. The collective odds ratios, along with their corresponding 95% confidence intervals, were calculated and presented to assess the robustness of the observed associations. Results: A total of seven studies involving controls and cases out of recorded 1265 controls and 1154 cases were analyzed to ascertain the significant association of the TIMP2 gene with urologic cancer. No statistically significant correlation was observed between allelic, recessive, dominant, and overdominant models for the genetic variant under investigation. A 95% confidence interval (CI) and odds ratio (OR) were computed for each model, considering p-values <0.05. The OR and 95% CI for the allelic model were 0.99 and 0.77-1.27, respectively, whereas the respective values were 1.00 and 0.76-1.32 for the recessive model. In the dominant contrast model, OR and 95% CI were 1.09 and 0.62-1.90, while the same were 0.93 and 0.77-1.12 for the overdominant model. A funnel plot was used to reanalyze and detect the results as statically satisfactory. Conclusions: As a result of the data obtained, the TIMP2 gene polymorphism does not correlate statistically with cancer risk. The significance of this finding can only be confirmed using a large population, extensive epidemiological research, a comprehensive survey, and a better understanding of the molecular pathways associated.

Exosomal circRNAs: Novel biomarkers and therapeutic targets for urinary tumors.

Exosomal circRNAs have emerged as promising biomarkers and therapeutic targets for urinary tumors. In this review, we explored the intricate role of exosomal circRNAs in urological cancers, focusing on their biological functions, dysregulation in tumors, and potential clinical applications. The review delves into the mechanisms by which exosomal circRNAs contribute to tumor progression and highlights their diagnostic and therapeutic implications. By synthesizing current research findings, we present a compelling case for the significance of exosomal circRNAs in the context of urinary tumors. Furthermore, the review discusses the challenges and opportunities associated with utilizing exosomal circRNAs as diagnostic tools and targeted therapeutic agents. There is a need for further research to elucidate the specific mechanisms of exosomal circRNA secretion and delivery, as well as to enhance the detection methods for clinical translational applications. Overall, this comprehensive review underscores the pivotal role of exosomal circRNAs in urinary tumors and underscores their potential as valuable biomarkers and therapeutic tools in the management of urological cancers.

TGFB1I1 promotes cell proliferation and migration in urothelial carcinoma.

Urothelial carcinoma (UC) is common cancer worldwide with a high prevalence in Taiwan, especially in the upper urinary tract, including the renal pelvis and ureter, also classifying as upper urinary tract urothelial carcinoma. Here, we aim to find a representative prognostic marker that strongly correlates to this type of carcinoma. Transforming growth factor beta-1-induced transcript 1 (TGFB1I1) is a cofactor of cellular TGF-ß1 and interacts with various nuclear receptors. The previous study showed that TGFB1I1 promotes focal adhesion formation, contributing to the epithelial-mesenchymal transition (EMT) with actin cytoskeleton and vimentin through TGFB1I1 regulation. We aim to reveal the role of TGFB1I1 in the tumorigenesis of UC. In silico and clinicopathological data of upper urinary tract urothelial carcinoma (UTUC) and urinary bladder urothelial carcinoma (UBUC) were accessed and analyzed for IHC staining regarding tumor characteristics, including survival outcome. Finally, an in vitro study was performed to demonstrate the biological changes of UC cells. In UTUC, overexpression of TGFB1I1 was significantly correlated with advanced tumor stage, papillary configuration, and frequent mitosis. Meanwhile, overexpression of TGFB1I1 was significantly correlated with advanced tumor stage and histological grade in UBUC. Moreover, the in vitro study shows that TGFB1I1 affects cell proliferation, viability, migration and wound healing. The EMT markers also decreased upon TGFB1I1 knockdown. In this study, we identified that TGFB1I1 regulates UC cell proliferation and viability and induces the EMT to facilitate cell migration in vitro, leading to its essential role in promoting tumor aggressiveness in both UTUC and UBUC.

Cyclin A2 Expression as Predictive Biomarker in Muscle-Invasive Upper Tract Urothelial Carcinoma.

INTRODUCTION: The aim was to evaluate the prognostic value of altered Cyclin A2 (CCNA2) gene expression in upper tract urothelial carcinoma (UTUC) and to assess its predictive potential as a prognostic factor for overall survival (OS) and disease-free survival. METHODS: 62 patients who underwent surgical treatment for UTUC were included. Gene expression of CCNA2, MKI67, and p53 was analyzed by quantitative reverse transcriptase polymerase chain reaction. Survival analyses were performed using the Kaplan-Meier method and the log-rank test. For Cox regression analyses, uni- and multivariable hazard ratios were calculated. Spearman correlation was used to analyze correlation of CCNA2 expression with MKI67 and p53. RESULTS: The median age of the cohort was 73 years, and it consisted of 48 males (77.4%) and 14 females (22.6%). Patients with high CCNA2 expression levels showed longer OS (HR 0.33; 95% CI: 0.15-0.74; p = 0.0073). Multivariable Cox regression analyses identified CCNA2 overexpression (HR 0.37; 95% CI: 0.16-0.85; p = 0.0189) and grading G2 (vs. G3) (HR 0.39; 95% CI: 0.17-0.87; p = 0.0168) to be independent predictors for longer OS. CCNA2 expression correlated positively with MKI67 expression (Rho = 0.4376, p = 0.0005). CONCLUSION: Low CCNA2 expression is significantly associated with worse OS. Thus, CCNA2 might serve as a potential biomarker in muscle-invasive UTUC and may be used to characterize a subset of patients having an unfavorable outcome and for future risk assessment scores.

Predictive and prognostic biomarkers in urological tumours.

Advancements in cutting-edge molecular profiling techniques, such as next-generation sequencing and bioinformatic analytic tools, have allowed researchers to examine tumour biology in detail and stratify patients based on factors linked with clinical outcome and response to therapy. This manuscript highlights the most relevant prognostic and predictive biomarkers in kidney, bladder, prostate and testicular cancers with recognised impact in clinical practice. In bladder and prostate cancer, new genetic acquisitions concerning the biology of tumours have modified the therapeutic scenario and led to the approval of target directed therapies, increasing the quality of patient care. Thus, it has become of paramount importance to choose adequate molecular tests, i.e., FGFR screening for urothelial cancer and BRCA1-2 alterations for prostate cancer, to guide the treatment plan for patients. While no tissue or blood-based biomarkers are currently used in routine clinical practice for renal cell carcinoma and testicular cancers, the field is quickly expanding. In kidney tumours, gene expression signatures might be the key to identify patients who will respond better to immunotherapy or anti-angiogenic drugs. In testicular germ cell tumours, the use of microRNA has outperformed conventional serum biomarkers in the diagnosis of primary tumours, prediction of chemoresistance, follow-up monitoring, and relapse prediction.

Molecular Urothelial Tumor Cell Subtypes Remain Stable During Metastatic Evolution.

Urothelial cancer (UC) care is moving toward precision oncology. For tumor biology-driven treatment of metastatic UC (mUC), molecular subtypes play a crucial role. However, it is not known whether subtypes change during metastatic evolution. To address this, we analyzed a UC progression cohort (N = 154 patients) with 138 matched primary tumors (PRIM) and synchronous or metachronous distant metastasis (MET) by immunohistochemistry, and mRNA sequencing in a subgroup of 20 matched pairs. Protein-based tumor cell subtypes and histomorphology remained stable during metastatic progression (concordance: 94%, 95% confidence interval [CI] 88-97%). In comparison, transcriptome-based molecular consensus subtypes exhibited higher heterogeneity between PRIM and MET (concordance: 45%, 95% CI 23-69%), with switches particularly occurring between luminal and stroma-rich tumors. Of note, all tumors classified as stroma rich showed luminal tumor cell differentiation. By an in-depth analysis, we found a negative correlation of luminal gene and protein expression with increasing desmoplastic stroma content, suggesting that luminal tumor cell differentiation of "stroma-rich tumors" is superimposed by gene expression signals stemming from the stromal compartment. Immunohistochemistry allows tumor cell subtyping into luminal, basal, or neuroendocrine classes that remain stable during metastatic progression. These findings expand our biological understanding of UC MET and have implications for future subtype-stratified clinical trials in patients with mUC. PATIENT SUMMARY: Urothelial carcinomas (UCs) occur in different appearances, the so-called molecular subtypes. These molecular subtypes will gain importance for the therapy of metastatic UCs in the future. We could demonstrate that the subtype remains stable during metastasis, which is highly relevant for future studies.

Patients with periodontitis might increase the risk of urologic cancers: a bidirectional two-sample Mendelian randomization study.

BACKGROUND: Numerous observational epidemiological studies have reported a bidirectional relationship between periodontitis and urological cancers. However, the causal link between these two phenotypes remains uncertain. This study aimed to examine the bidirectional causal association between periodontitis and four types of urological tumors, specifically kidney cancer (KC), prostate cancer (PC), bladder cancer (BC), and testis cancer (TC). METHODS: Based on large-scale genome-wide association study (GWAS) data, we utilized the two-sample Mendelian randomization (MR) approach to evaluate causal relationships between periodontitis and urological cancers. Several MR methods covering various consistency assumptions were applied in this study, including contamination mixture and Robust Adjusted Profile Score to obtain robust results. Summary-level data of individuals with European ancestry were extracted from the UK Biobank, the Kaiser GERA cohorts, and the FinnGen consortium. RESULTS: Our findings revealed significant positive genetic correlations between periodontitis and kidney cancer (OR 1.287; 95% CI 1.04, 1.594; P = 0.020). We did not find a significant association of periodontitis on prostate cancer, bladder cancer, and testis cancer. In reverse MR, no significant results were observed supporting the effect of urologic cancers on periodontitis (all P > 0.05). CONCLUSION: Our study provides the evidence of a potential causal relationship between periodontitis and kidney cancer. However, large-scale studies are warranted to confirm and elucidate the underlying mechanisms of this association.

Urinary tract cytology showing variant morphology and divergent differentiation.

Urothelial carcinoma represents a diverse group of tumours with distinct histologic subtypes, each exhibiting unique cytomorphologic features, architectural growth patterns, and/or well-developed aberrant differentiation. In fact, there are more than 13 subtypes of urothelial carcinoma recognized in the 2022 WHO classification of tumours in the urinary tract. The identification of these subtypes is crucial for an accurate diagnosis of urothelial carcinoma, and many have important clinical implications. Variant/divergent features may coexist with conventional high-grade urothelial carcinoma (HGUC) or present with 100% variant morphology. In urinary tract cytology (UTC), urothelial carcinoma can display divergent differentiation, such as squamous, glandular, or small cell carcinoma differentiation. The use of cell block preparations and immunohistochemistry with available residual urine can enhance diagnostic accuracy. On the other hand, identifying urothelial carcinoma variants, including nested, micropapillary, and plasmacytoid subtypes, poses significant challenges in UTC. Many cases of these variants are only detected retrospectively after variant histology has been established from resection specimens. Moreover, some variants exhibit features inconsistent with the diagnostic criteria for HGUC according to the Paris System for Reporting Urinary Tract Cytology. Nevertheless, the rarity of pure variant morphology and the occurrence of some false negatives for these variant cases are essential to maintain the specificity of UTC overall. This review covers the histology, cytomorphology, and important clinical aspects observed in urothelial carcinoma exhibiting divergent differentiation and various urothelial carcinoma variants detected in UTC.

Smartphone-Based Fluorescent Profiling of Quaternary MicroRNAs in Urine for Rapid Diagnosis of Urological Cancers Using a Multiplexed Isothermal Exponential Amplification Reaction.

Urological cancers such as bladder or prostate cancer represent one of the most malignant tumors that accounts for an extremely high mortality. However, conventionally standard diagnostics for urological cancers are hardly available in low-resource settings. We developed herein a hand-held fluorescent imaging platform by integrating a multiplexed isothermal exponential amplification reaction (EXPAR) with a microgel-enriched methodology for sensitive profiling of quaternary microRNAs (miRNAs) in urine and quick diagnosis of urological cancers at the early stage. The target miRNA mixtures in the urine underwent four parallel EXPARs without cross-reactivity, followed by surface concentration and hybridization by the encoded polyacrylamide microgels. This mix-and-read strategy allowed for one-pot analysis of several key miRNAs simultaneously and provided 5-fold enhancement in fluorescent detection sensitivities compared to the individual EXPAR-based assays. Four urinary miRNAs (let-7a, miRNA-155, -223, and -143) could be quantitatively determined in a wide linear range from 50 fM to 30 nM, with the limits of detection at femtomolar levels. Using a smartphone-based imaging microreader, healthy and cancerous cohorts with prostate, bladder, and renal cell cancers could be discriminated in 30 min with the accuracy >83% using linear discriminant analysis. The developed detection platform has proven to be a portable, noninvasive, and useful complement to the toolbox for miRNA-based liquid biopsies, which holds immense potential and advantage for regular and large-scale applications in early cancer diagnosis.

Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers.

Urological cancer encompasses a diverse range of tumors, including bladder, prostate, renal, upper urinary tract, and germ cell tumors [...].

OncoUroMiR: Circulating miRNAs for Detection and Discrimination of the Main Urological Cancers Using a ddPCR-Based Approach.

The three most common genitourinary malignancies (prostate/kidney/bladder cancers) constitute a substantial proportion of all cancer cases, mainly in the elderly population. Early detection is key to maximizing the patients' survival, but the lack of highly accurate biomarkers that might be used through non-/minimally invasive methods has impaired progress in this domain. Herein, we sought to develop a minimally invasive test to detect and discriminate among those urological cancers based on miRNAs assessment through ddPCR. Plasma samples from 268 patients with renal cell (RCC; n = 119), bladder (BlCa; n = 73), and prostate (PCa; n = 76) carcinomas (UroCancer group), and 74 healthy donors were selected. Hsa-miR-126-3p, hsa-miR-141-3p, hsa-miR-153-5p, hsa-miR-155-5p, hsa-miR-182-5p, hsa-miR-205-5p, and hsa-miR-375-3p levels were assessed. UroCancer cases displayed significantly different circulating hsa-miR-182-5p/hsa-miR-375-3p levels compared to healthy donors. Importantly, the hsa-miR-155-5p/hsa-miR-375-3p panel detected RCC with a high specificity (80.54%) and accuracy (66.04%). Furthermore, the hsa-miR-126-3p/hsa-miR-375-3p panel identified BlCa with a 94.87% specificity and 76.45% NPV whereas higher hsa-miR-126-3p levels were found in PCa patients. We concluded that plasma-derived miRNAs can identify and discriminate among the main genitourinary cancers, with high analytical performance. Although validation in a larger cohort is mandatory, these findings demonstrate that circulating miRNA assessment by ddPCR might provide a new approach for early detection and risk stratification of the most common urological cancers.

A Large Genetic Causal Analysis of the Gut Microbiota and Urological Cancers: A Bidirectional Mendelian Randomization Study.

BACKGROUND: Several observational studies and clinical trials have shown that the gut microbiota is associated with urological cancers. However, the causal relationship between gut microbiota and urological cancers remains to be elucidated due to many confounding factors. METHODS: In this study, we used two thresholds to identify gut microbiota GWAS from the MiBioGen consortium and obtained data for five urological cancers from the UK biobank and Finngen consortium, respectively. We then performed a two-sample Mendelian randomization (MR) analysis with Wald ratio or inverse variance weighted as the main method. We also performed comprehensive sensitivity analyses to verify the robustness of the results. In addition, we performed a reverse MR analysis to examine the direction of causality. RESULTS: Our study found that family Rikenellaceae, genus Allisonella, genus Lachnospiraceae UCG001, genus Oscillibacter, genus Eubacterium coprostanoligenes group, genus Eubacterium ruminantium group, genus Ruminococcaceae UCG013, and genus Senegalimassilia were related to bladder cancer; genus Ruminococcus torques group, genus Oscillibacter, genus Barnesiella, genus Butyricicoccus, and genus Ruminococcaceae UCG005 were related to prostate cancer; class Alphaproteobacteria, class Bacilli, family Family XI, genus Coprococcus2, genus Intestinimonas, genus Lachnoclostridium, genus Lactococcus, genus Ruminococcus torques group, and genus Eubacterium brachy group were related to renal cell cancer; family Clostridiaceae 1, family Christensenellaceae, genus Eubacterium coprostanoligenes group, genus Clostridium sensu stricto 1, and genus Eubacterium eligens group were related to renal pelvis cancer; family Peptostreptococcaceae, genus Romboutsia, and genus Subdoligranulum were related to testicular cancer. Comprehensive sensitivity analyses proved that our results were reliable. CONCLUSIONS: Our study confirms the role of specific gut microbial taxa on urological cancers, explores the mechanism of gut microbiota on urological cancers from a macroscopic level, provides potential targets for the screening and treatment of urological cancers, and is dedicated to providing new ideas for clinical research.

The current landscape of m6A modification in urological cancers.

N6-methyladenosine (m6A) methylation is a dynamic and reversible procession of epigenetic modifications. It is increasingly recognized that m6A modification has been involved in the tumorigenesis, development, and progression of urological tumors. Emerging research explored the role of m6A modification in urological cancer. In this review, we will summarize the relationship between m6A modification, renal cell carcinoma, bladder cancer, and prostate cancer, and discover the biological function of m6A regulators in tumor cells. We will also discuss the possible mechanism and future application value used as a potential biomarker or therapeutic target to benefit patients with urological cancers.