Investigating the Shared Genetic Architecture Between Leukocyte Telomere Length and Prostate Cancer.

PURPOSE: Evidence of an association between leukocyte telomere length (LTL) and prostate cancer (PCa) is accumulating; however, their shared genetic basis remains unclear. MATERIALS AND METHODS: Using summary statistics obtained from the genome-wide association study (GWAS), we quantified the global and local genetic correlations between two traits. Subsequently, we identified potential pleiotropic loci, common tissue-enriched regions, and risk gene loci while inferring assumed causal relationships. RESULTS: Our study demonstrated a global genetic correlation between LTL and PCa (genetic correlation=0.066, p=0.017), which was further confirmed in local genomic regions. Cross-trait GWAS meta-analysis revealed 44 shared loci, including 10 novel pleiotropic single nucleotide polymorphisms appearing concurrently in significant local genetic correlation regions. Notably, two new loci (rs9419958; rs3730668) were additionally validated to co-localize. For the first time, we identified a significant shared genetic enrichment of both traits in the small intestine tissue at the terminal ileum, with functional genes in this region affecting both LTL and PCa. Concurrently, Mendelian randomization analysis indicated a positive causal relationship between LTL and PCa. CONCLUSIONS: In conclusion, our study makes a significant contribution to the ongoing debate concerning the potential association between longer LTL and a higher risk of PCa. Additionally, we provide new evidence for the development of therapeutic targets for PCa and propose new directions for future risk prediction in this regard.

Proteomic and phosphoproteomic landscape of localized prostate cancer unveils distinct molecular subtypes and insights into precision therapeutics.

Building upon our previous investigation of genomic, epigenomic, and transcriptomic profiles of prostate cancer in China, we conducted a comprehensive analysis of proteomic and phosphoproteomic profiles of 82 tumor tissues and matched adjacent normal tissues from 41 Chinese patients with localized prostate cancer. We identified three distinct proteomic subtypes with significant difference in both molecular features and clinical prognosis. Notably, these proteomic subtypes exhibited a parallel degree of heterogeneity in the phosphoproteome, featuring unique metabolism, proliferation, and immune infiltration characteristics. We further demonstrated that a combination of proteins and phosphosites serves as the most effective biomarkers in prostate cancer to predict biochemical recurrence. Through an integrated multiomics analysis, we revealed mechanistic differences underlying different proteomic subtypes and highlighted the potential significance of Serine/arginine-rich splicing factor 1 (SRSF1) phosphorylation in promoting the malignant characteristics of prostate cancer cells. Our multiomics data provide valuable resources for understanding the molecular mechanisms of prostate cancer within the Chinese population, which have the potential to inform the development of personalized treatment strategies and enhance prognostic analyses for prostate cancer patients.

Proteomic landscape profiling of primary prostate cancer reveals a 16-protein panel for prognosis prediction.

Prostate cancer (PCa) is the most common malignant tumor in men. Currently, there are few prognosis indicators for predicting PCa outcomes and guiding treatments. Here, we perform comprehensive proteomic profiling of 918 tissue specimens from 306 Chinese patients with PCa using data-independent acquisition mass spectrometry (DIA-MS). We identify over 10,000 proteins and define three molecular subtypes of PCa with significant clinical and proteomic differences. We develop a 16-protein panel that effectively predicts biochemical recurrence (BCR) for patients with PCa, which is validated in six published datasets and one additional 99-biopsy-sample cohort by targeted proteomics. Interestingly, this 16-protein panel effectively predicts BCR across different International Society of Urological Pathology (ISUP) grades and pathological stages and outperforms the D'Amico risk classification system in BCR prediction. Furthermore, double knockout of NUDT5 and SEPTIN8, two components from the 16-protein panel, significantly suppresses the PCa cells to proliferate, invade, and migrate, suggesting the combination of NUDT5 and SEPTIN8 may provide new approaches for PCa treatment.

Hypermethylated TAGMe as a universal-cancer-only methylation marker and its application in diagnosis and recurrence monitoring of urothelial carcinoma.

BACKGROUND: Urothelial carcinoma (UC) is the second most common urological malignancy. Despite numerous molecular markers have been evaluated during the past decades, no urothelial markers for diagnosis and recurrence monitoring have shown consistent clinical utility. METHODS: The methylation level of tissue samples from public database and clinical collected were analyzed. Patients with UC and benign diseases of the urinary system (BUD) were enrolled to establish TAGMe (TAG of Methylation) assessment in a training cohort (n = 567) using restriction enzyme-based bisulfite-free qPCR. The performance of TAGMe assessment was further verified in the validation cohort (n = 198). Urine samples from 57 UC patients undergoing postoperative surveillance were collected monthly for six months after surgery to assess the TAGMe methylation. RESULTS: We identified TAGMe as a potentially novel Universal-Cancer-Only Methylation (UCOM) marker was hypermethylated in multi-type cancers and investigated its application in UC. Restriction enzyme-based bisulfite-free qPCR was used for detection, and the results of which were consistent with gold standard pyrosequencing. Importantly, hypermethylated TAGMe showed excellent sensitivity of 88.9% (95% CI: 81.4-94.1%) and specificity of 90.0% (95% CI: 81.9-95.3%) in efficiently distinguishing UC from BUD patients in urine and also performed well in different clinical scenarios of UC. Moreover, the abnormality of TAGMe as an indicator of recurrence might precede clinical recurrence by three months to one year, which provided an invaluable time window for timely and effective intervention to prevent UC upstaging. CONCLUSION: TAGMe assessment based on a novel single target in urine is effective and easy to perform in UC diagnosis and recurrence monitoring, which may reduce the burden of cystoscopy. Trial registration ChiCTR2100052507. Registered on 30 October 2021.

Explainable machine learning predicts survival of retroperitoneal liposarcoma: A study based on the SEER database and external validation in China.

OBJECTIVE: We have developed explainable machine learning models to predict the overall survival (OS) of retroperitoneal liposarcoma (RLPS) patients. This approach aims to enhance the explainability and transparency of our modeling results. METHODS: We collected clinicopathological information of RLPS patients from The Surveillance, Epidemiology, and End Results (SEER) database and allocated them into training and validation sets with a 7:3 ratio. Simultaneously, we obtained an external validation cohort from The First Affiliated Hospital of Naval Medical University (Shanghai, China). We performed LASSO regression and multivariate Cox proportional hazards analysis to identify relevant risk factors, which were then combined to develop six machine learning (ML) models: Cox proportional hazards model (Coxph), random survival forest (RSF), ranger, gradient boosting with component-wise linear models (GBM), decision trees, and boosting trees. The predictive performance of these ML models was evaluated using the concordance index (C-index), the integrated cumulative/dynamic area under the curve (AUC), and the integrated Brier score, as well as the Cox-Snell residual plot. We also used time-dependent variable importance, analysis of partial dependence survival plots, and the generation of aggregated survival SHapley Additive exPlanations (SurvSHAP) plots to provide a global explanation of the optimal model. Additionally, SurvSHAP (t) and survival local interpretable model-agnostic explanations (SurvLIME) plots were used to provide a local explanation of the optimal model. RESULTS: The final ML models are consisted of six factors: patient's age, gender, marital status, surgical history, as well as tumor's histopathological classification, histological grade, and SEER stage. Our prognostic model exhibits significant discriminative ability, particularly with the ranger model performing optimally. In the training set, validation set, and external validation set, the AUC for 1, 3, and 5 year OS are all above 0.83, and the integrated Brier scores are consistently below 0.15. The explainability analysis of the ranger model also indicates that histological grade, histopathological classification, and age are the most influential factors in predicting OS. CONCLUSIONS: The ranger ML prognostic model exhibits optimal performance and can be utilized to predict the OS of RLPS patients, offering valuable and crucial references for clinical physicians to make informed decisions in advance.

Involving logical clinical knowledge into deep neural networks to improve bladder tumor segmentation.

Segmentation of bladder tumors from medical radiographic images is of great significance for early detection, diagnosis and prognosis evaluation of bladder cancer. Deep Convolution Neural Networks (DCNNs) have been successfully used for bladder tumor segmentation, but the segmentation based on DCNN is data-hungry for model training and ignores clinical knowledge. From the clinical view, bladder tumors originate from the mucosal surface of bladder and must rely on the bladder wall to survive and grow. This clinical knowledge of tumor location is helpful to improve the bladder tumor segmentation. To achieve this, we propose a novel bladder tumor segmentation method, which incorporates the clinical logic rules of bladder tumor and bladder wall into DCNNs to harness the tumor segmentation. Clinical logical rules provide a semantic and human-readable knowledge representation and are easy for knowledge acquisition from clinicians. In addition, incorporating logical rules of clinical knowledge helps to reduce the data dependency of the segmentation network, and enables precise segmentation results even with limited number of annotated images. Experiments on bladder MR images collected from the collaborating hospital validate the effectiveness of the proposed bladder tumor segmentation method.

Survival nomogram and risk classification system for patients with adrenocortical carcinoma: a study based on the SEER database and external validation in China.

Background: Adrenocortical carcinoma (ACC) is an extremely rare and highly invasive malignant tumor. However, there is currently no reliable method to predict the prognosis of ACC. Our objective is to construct a nomogram and a risk classification system to predict the 1-year, 3-year, and 5-year overall survival (OS) of ACC. Methods: We retrieved clinicopathological data of patients diagnosed with ACC in The Surveillance, Epidemiology, and End Results (SEER) database and divided them into training and validation cohorts with a 7:3 ratio. Simultaneously, we collected an external validation cohort from The First Affiliated Hospital of Naval Medical University (Shanghai, China). Univariate and multivariate Cox analyses were performed to identify relevant risk factors, which were then combined to develop a correlation nomogram. The predictive performance of the nomogram was evaluated using the concordance index (C-index), receiver-operating characteristic curve (ROC), and calibration curves. Decision curve analysis (DCA) was applied to assess the clinical utility of the nomogram. In addition, Kaplan-Meier survival curves were generated to demonstrate the variation in OS between groups. Results: The final nomogram consisted of five factors: age, T, N, M, and history of chemotherapy. Our prognostic model demonstrated significant discriminative ability, with C-index and the area under the receiver operating characteristic (AUC) values exceeding 0.70. Additionally, DCA validated the clinical utility of the nomogram. In the entire cohort, the median OS for patients in the low- and high-risk groups was 70 and 10 months, respectively. Conclusions: A nomogram and a corresponding risk classification system were developed in order to predict the OS of patients diagnosed with ACC. These tools have the potential to provide valuable support for patient counseling and assist in the decision-making process related to treatment options.

Establishment of bladder cancer spheroids and cultured in microfluidic platform for predicting drug response.

Cisplatin-containing combination chemotherapy has been used as the standard treatment for bladder cancer patients at advanced stage. However, nearly 50% of patients are nonresponders. To guide the selection of more effective chemotherapeutic agents, a bladder cancer spheroids microfluidic drug sensitivity analysis system was established in this study. Bladder cancer spheroids were established and successfully cultured in a customized microfluidic device to assess their response to different chemotherapeutic agents. The in vitro drug sensitivity results were also compared to patient-derived xenograft (PDX) models and clinical responses of patients. As a result, bladder cancer spheroids faithfully recapitulate the histopathological and genetic features of their corresponding parental tumors. Furthermore, the in vitro drug sensitivity outcomes of spheroids (n = 8) demonstrated a high level of correlation with the PDX (n = 2) and clinical response in patients (n = 2). Our study highlights the potential of combining bladder cancer spheroids and microfluidic devices as an efficient and accurate platform for personalized selection of chemotherapeutic agents.

Patients With Muscle-Invasive Bladder Cancer With Lymphovascular Invasion in Transurethral Resection Specimen Benefits Most From Platinum-Based Neoadjuvant Chemotherapy.

PURPOSE: The survival benefit of neoadjuvant chemotherapy (NAC) before definitive radical cystectomy (RC) varied among patients, suggesting proper selection of patients for NAC to maximize the survival benefit. This study aimed to investigate the role of lymphovascular invasion (LVI) in transurethral resection (TUR) specimens in selecting patients with MIBC for NAC. METHODS: Two retrospective cohorts of patients with cT2-4aN0 MIBC who underwent RC from 2004 to 2015 provided by Lund University were included. Inverse probability weighting was applied to make the NAC-treated (NAC) and untreated (non-NAC) cohorts comparable. Survival benefits were estimated with Kaplan-Meier curves and Cox proportional hazards models. The primary endpoint was cancer-specific survival (CSS). LVI in TUR specimens and molecular taxonomies (BASE47, UNC, and LundTax) were examined, and bulk RNA-seq datasets were explored for LVI-relevant signatures. RESULTS: A total of 341 patients with cT2-4aN0 MIBC were included. The NAC cohort included 125 patients, whereas the non-NAC cohort included 216 patients. The 3-year CSS benefit of NAC was 7.1%. For patients with positive LVI in TUR specimens, the 3-year CSS benefit of NAC was 26.2% (48.1% vs. 74.3%), with a risk reduction of 56% (HR = 0.44, P = .03). A sensitivity analysis confirmed a significant interaction between LVI and NAC. This study failed to identify the molecular subtypes that maximized the survival benefit of NAC. Exploration of LVI-relevant signatures remains inconclusive. CONCLUSIONS: LVI in TUR specimens could help identify patients with MIBC who would derive maximal survival benefit from NAC. Further prospective validation is necessary.

Comprehensive identification of onco-exaptation events in bladder cancer cell lines revealed L1PA2-SYT1 as a prognosis-relevant event.

Transposable elements (TEs) can provide ectopic promoters to drive the expression of oncogenes in cancer, a mechanism known as onco-exaptation. Onco-exaptation events have been extensively identified in various cancers, with bladder cancer showing a high frequency of onco-exaptation events (77%). However, the effect of most of these events in bladder cancer remains unclear. This study identified 44 onco-exaptation events in 44 bladder cancer cell lines in 137 RNA-seq datasets from six publicly available cohorts, with L1PA2 contributing the most events. L1PA2-SYT1, L1PA2-MET, and L1PA2-XCL1 had the highest frequency not only in cell lines but also in TCGA-BLCA samples. L1PA2-SYT1 showed significant tumor specificity and was found to be activated by CpG island demethylation in its promoter. The upregulation of L1PA2-SYT1 enhances the in vitro invasion of bladder cancer and is an independent risk factor for patient's overall survival, suggesting L1PA2-SYT1 being an important event that promotes the development of bladder cancer.

Value of digital rectal examination in patients with suspected prostate cancer: a prospective cohort analysis study.

Background: Digital rectal examination (DRE) is a straightforward, cost-effective, practical, and time-honored physical examination method that plays a valuable role in the detection of prostate cancer (PCa). Nevertheless, with the advent of the prostate-specific antigen (PSA) era, the necessity of performing DRE has become a subject of debate. Our aim was to investigate the diagnostic efficacy and adjunctive role of DRE in a population (Prostate Imaging Reporting and Data System (PI-RADS), PI-RADS ≥3 or PSA ≥4 ng/mL) suspected of PCa. Methods: Five hundred and ninety-seven patients with suspected PCa requiring referral for biopsy were prospectively enrolled consecutively from February 2020 to May 2021. All patients received DRE and corresponding clinical diagnosis by a urologist before biopsy. According to the collected clinical and pathological information, the diagnostic performance of DRE in different PSA stratifications, and its association with tumor location and Gleason score (GS) were statistically analyzed. Results: Among patients with suspected cancer, the diagnostic accuracy of DRE was 63.45%. Compared with central zone or transition zone tumors, the recall rate of peripheral zone PCa with DRE-positive results was higher (65.50% vs. 34.55%). DRE-positive results were significantly correlated with GS ≥7 PCa (P<0.001), and the average GS of DRE-positive PCa patients was significantly higher than that of DRE-negative (7.92 vs. 7.11, P<0.001). Conclusions: DRE may help physicians further judge the necessity of biopsy in patients with elevated PSA, and preliminarily estimate the location and invasiveness of the tumor. However, it is still necessary to explore the value of DRE in a normal PSA population.

Association between testosterone and cancers risk in women: a two-sample Mendelian randomization study.

OBJECTIVE: Previous observational studies have explored the correlation between testosterone and cancer risk. However, the causal association between testosterone and various cancer types in women remains inconclusive. The objective of this Mendelian randomization study is to evaluate the causal links between total testosterone (TT) and bioavailable testosterone (BT) with cancer risk in females. METHODS: Initially, a rigorous quality control process was employed to identify suitable instrumental single nucleotide polymorphisms (SNPs) associated with the exposure under investigation that exhibited a significant association. The genetic causal relationship between female testosterone levels and the risk of developing cancers was examined through a two-sample Mendelian randomization. Various analytical methods, including inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode, were applied in the investigation. Key findings were primarily based on the results obtained via IVW (random effects), and sensitivity analyses were conducted to assess the reliability of the obtained results. Furthermore, maximum likelihood, penalized weighted median, and IVW (fixed effects) methods were utilized to further validate the robustness of the results. RESULTS: Based on the results of IVW analysis, our study indicated a positive causal relationship between BT and breast cancer (OR = 1.1407, 95%CI: 1.0627-1.2244, P = 0.0015) and endometrial cancer (OR = 1.4610, 95%CI: 1.2695-1.6813, P = 1.22E-06). Moreover, our findings also showed a positive causal association between TT and breast cancer (OR = 1.1764, 95%CI: 1.0846-1.2761, P = 0.0005), cervical cancer(OR = 1.0020, 95%CI: 1.0007-1.0032, P = 0.0077), and endometrial cancer(OR = 1.4124, 95%CI: 1.2083-1.6511, P = 0.0001). Additionally, our results demonstrated a negative causal relationship between BT and ovarian cancer (OR = 0.8649, 95%CI: 0.7750-0.9653, P = 0.0320). However, no causal relationship was found between BT, TT and other types of cancer (corrected P > 0.05). CONCLUSIONS: This study elucidates the role of testosterone on the development of breast cancer, endometrial cancer, ovarian cancer, and cervical cancer. It also hints at a potential but fragile link between testosterone and bladder cancer, as well as thyroid cancer. Nonetheless, it's worth noting that no statistically significant relationship between testosterone and various other types of cancer in females was identified.

Preoperative urine sediment chromosomal instability level predicts urothelial cancer prognosis.

PURPOSE: Urothelial carcinomas (UCs) are often characterized by frequent recurrences after surgery, making UC one of the costliest cancers. Chromosomal instability (CIN) has been proven to be a hallmark of UCs and is related to the prognosis of many cancer types. In this study, we evaluated CIN of urine sediments as a prognostic indicator for UCs. METHODS: Patients with UC were prospectively recruited. Preoperative urine samples were collected for whole genome sequencing and urine cytology tests. Patients underwent standard-of-care treatment and were followed up until disease relapse or study ended. Concordance and accuracy of CIN alone or in combination with cytology in predicting disease relapse were assessed. The value of CIN combined with European Organization for Research and Treatment of Cancer (EORTC) model were also analyzed. RESULTS: A total of 137 patients with UCs were included in this study. Median follow-up was 44.2 months and 41.61% patients suffered from cancer relapse. Patients with CIN-high indicated higher relapse rate, and this distinction was significant for patients underwent transurethral resection of bladder tumor (57.89% vs. 34.29%, P = 0.016). Combination of cytology and CIN result could further classified patients into subgroups with distinct relapse risks. Meanwhile, the combination of CIN and EORTC model significantly improved the prediction accuracy compared with EORTC alone (Harrel's C-index: 0.71 vs. 0.65). CONCLUSION: CIN level of preoperative urine exfoliated cells had robust prognostic value for bladder cancer patients underwent TURBT. The prognostic model by combining CIN and EORTC may help in stratifying patients to optimize follow-up regimen.

The natural course of bacillus Calmette-Guérin induced bladder lesions: A long-term follow-up study and systematic review.

Objective: Bacillus Calmette-Guérin (BCG) instillation is the standard adjuvant treatment for intermediate- and high-risk non-muscle-invasive bladder cancer after transurethral resection. Nevertheless, its toxicity often causes bladder complications. On follow-up cystoscopy, post-BCG bladder lesions can be pathologically benign, urothelial carcinoma recurrence, or other types of bladder malignancy. Only a small number of case reports have been published on post-BCG bladder lesions. Their clinical features, natural course, and management remain unknown. Methods: We retrospectively studied cystoscopic videos and medical records of BCG-treated bladder cancer patients at our center. During a long-term follow-up, we took biopsies on tumor-like lesions and described their changes. In addition, we summarized previous studies on post-BCG bladder lesions by systematic literature searching and review. Results: We described a series of three cases with post-BCG bladder lesions mimicking tumor recurrence from a total of 38 cases with follow-up data for more than 5 years. Those lesions could last, grow, or disappear spontaneously, and remain pathological benign for years. In systematic review, we identified and analyzed a total of 15 cases with post-BCG bladder lesions with detailed clinical information. Eleven of the 15 were benign and have a good prognosis with nephrogenic adenoma being the most common pathological type. Conclusion: Based on previous studies and our experience, benign lesions after BCG instillation cannot distinguish with cancer recurrence by cystoscopy alone, even under narrow band imaging mode. Nonetheless, given most of them have a good prognosis, random biopsy or transurethral resection might be spared in the patients with long-term negative biopsy and urine cytology.

E3 ubiquitin ligases and deubiquitinases in bladder cancer tumorigenesis and implications for immunotherapies.

With the rapidly increasing incidence of bladder cancer in China and worldwide, great efforts have been made to understand the detailed mechanism of bladder cancer tumorigenesis. Recently, the introduction of immune checkpoint inhibitor-based immunotherapy has changed the treatment strategy for bladder cancer, especially for advanced bladder cancer, and has improved the survival of patients. The ubiquitin-proteasome system, which affects many biological processes, plays an important role in bladder cancer. Several E3 ubiquitin ligases and deubiquitinases target immune checkpoints, either directly or indirectly. In this review, we summarize the recent progress in E3 ubiquitin ligases and deubiquitinases in bladder cancer tumorigenesis and further highlight the implications for bladder cancer immunotherapies.

Knockdown of kinesin family member 4A inhibits cell proliferation, migration, and invasion while promoting apoptosis of urothelial bladder carcinoma cells.

BACKGROUND: Kinesin family member 4A (KIF4A) is upregulated in a variety of cancers. However, its expression and potential downstream targets in urothelial bladder carcinoma (UBC) remain unclear. METHODS: Expression data of KIF4A in UBC and noncancerous tissues were downloaded from the GEPIA database. Cell proliferation, migration, invasion, and apoptosis of T24 and 5637 UBC cells were examined using wound healing, transwell, colony formation, CCK-8, and flow cytometry assays. KIF4A and potential downstream genes were analyzed using qRT-PCR, western blot analysis, and immunohistochemistry. RESULTS: In UBC samples, KIF4A expression was significantly higher than in corresponding noncancerous samples. UBC patients with high KIF4A expression had poor cancer-specific survival and overall survival. Knockdown of KIF4A significantly inhibited proliferation and promoted apoptosis of UBC cells, accompanied by dephosphorylation of AKT and increased the protein level of proapoptotic factors. Additionally, knockdown of KIF4A reduced migration and invasion of UBC cells whereas overexpression of KIF4A exhibited opposite effects, along with altered protein level in epithelial-mesenchymal transition-related genes. Furthermore, overexpression of YAP1 promoted KIF4A expression whereas knockdown of YAP1 suppressed KIF4A expression in UBC cells. Alternatively, KIF4A knockdown reduced YAP1 nuclear protein level whereas KIF4A overexpression suppressed YAP1 phosphorylation and facilitated YAP1 nuclear translocation. CONCLUSIONS: KIF4A upregulation correlates with poor prognosis of UBC. Knockdown of KIF4A inhibits proliferation, migration, and invasion of UBC cells while inducing apoptosis possibly through dephosphorylation of AKT, changes in EMT-related genes, and interaction with YAP1.