Identifying the role of MTHFD1L in prostate cancer progression from genetic analysis and experimental validation.

One-carbon metabolism plays a crucial role in tumorigenesis as it supplies the one-carbon units necessary for nucleotide synthesis, epigenetic regulation, and redox metabolism, ensuring the rapid proliferation of cancer cells. However, their roles in prostate cancer progression remain poorly understood. In this study, we investigated the association between genetic variants in the one-carbon metabolism pathway and clinical outcomes in patients receiving androgen deprivation therapy for prostate cancer. The associations of 130 single-nucleotide polymorphisms located within 14 genes involved in the one-carbon metabolism pathway with cancer-specific survival (CSS), overall survival, and progression-free survival were assessed using Cox regression in 630 patients with prostate cancer. Subsequently, functional studies were performed using prostate cancer cell lines. After adjusting for covariates and multiple testing, MTHFD1L rs2073190 was found to be significantly associated with CSS (P = 0.000184). Further pooled analysis of multiple datasets demonstrated that MTHFD1L was upregulated in prostate cancer and increased MTHFD1L expression was positively correlated with tumor aggressiveness and poor patient prognosis. Functionally, MTHFD1L knockdown suppressed prostate cancer cell proliferation and colony formation. RNA sequencing and pathway analysis revealed that differentially expressed genes were predominantly enriched in the cell cycle pathway. In conclusion, genetic variants in MTHFD1L of one-carbon metabolism may serve as promising predictors, and our findings offer valuable insights into the underlying genetic mechanisms of prostate cancer progression.

Integrated analysis identifies GABRB3 as a biomarker in prostate cancer.

BACKGROUND: Treatment failure following androgen deprivation therapy (ADT) presents a significant challenge in the management of advanced prostate cancer. Thus, understanding the genetic factors influencing this process could facilitate the development of personalized treatments and innovative therapeutic strategies. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in controlling cell growth and tumorigenesis. We hypothesized that genetic variants within this pathway may affect the clinical outcomes of patients undergoing ADT for prostate cancer. METHODS: We genotyped 399 single-nucleotide polymorphisms (SNPs) across 28 core PI3K/AKT pathway genes in a cohort of 630 patients with prostate cancer undergoing ADT. We assessed the potential association of the SNPs with patient survival. Functional analyses of the implicated genes were also performed to evaluate their effects on prostate cancer. RESULTS: After multivariate Cox regression analysis and multiple testing correction, GABRB3 rs12591845 exhibited the most significant association with both overall and cancer-specific survivals (P < 0.003). A comprehensive pooled analysis of 16 independent gene expression datasets revealed elevated expression of GABRB3 in prostate cancer tissues compared to that in normal tissues (P < 0.001). Furthermore, gene set enrichment analysis unveiled differential enrichment of pathways such as myogenesis, interferon γ and α responses, and the MYC proto-oncogene pathway in tumors with elevated GABRB3 expression, implying a role for GABRB3 in prostate cancer. CONCLUSION: Our results suggest that rs12591845 could potentially serve as a valuable prognostic indicator for patients undergoing ADT. The potential role of GABRB3 in promoting prostate tumorigenesis is also highlighted.

ATP8B1: A prognostic prostate cancer biomarker identified via genetic analysis.

BACKGROUND: Controlling the asymmetric distribution of phospholipids across biological membranes plays a pivotal role in the life cycle of cells; one of the most important contributors that maintain this lipid asymmetry are phospholipid-transporting adenosine triphosphatases (ATPases). Although sufficient information regarding their association with cancer exists, there is limited evidence linking the genetic variants of phospholipid-transporting ATPase family genes to prostate cancer in humans. METHODS: In this study, we investigated the association of 222 haplotype-tagging single-nucleotide polymorphisms (SNPs) in eight phospholipid-transporting ATPase genes with cancer-specific survival (CSS) and overall survival (OS) of 630 patients treated with androgen-deprivation therapy (ADT) for prostate cancer. RESULTS: After multivariate Cox regression analysis and multiple testing correction, we found that ATP8B1 rs7239484 was remarkably associated with CSS and OS after ADT. A pooled analysis of multiple independent gene-expression datasets demonstrated that ATP8B1 was under-expressed in tumor tissues and that a higher ATP8B1 expression was associated with a better patient prognosis. Moreover, we established highly invasive sublines using two human prostate cancer cell lines to mimic cancer progression traits in vitro. The expression of ATP8B1 was consistently downregulated in both highly invasive sublines. CONCLUSION: Our study indicates that rs7239484 is a prognostic factor for patients treated with ADT and that ATP8B1 can potentially attenuate prostate cancer progression.

Alterations of Cytoskeleton Networks in Cell Fate Determination and Cancer Development.

Cytoskeleton proteins have been long recognized as structural proteins that provide the necessary mechanical architecture for cell development and tissue homeostasis. With the completion of the cancer genome project, scientists were surprised to learn that huge numbers of mutated genes are annotated as cytoskeletal or associated proteins. Although most of these mutations are considered as passenger mutations during cancer development and evolution, some genes show high mutation rates that can even determine clinical outcomes. In addition, (phospho)proteomics study confirms that many cytoskeleton-associated proteins, e.g., ß-catenin, PIK3CA, and MB21D2, are important signaling mediators, further suggesting their biofunctional roles in cancer development. With emerging evidence to indicate the involvement of mechanotransduction in stemness formation and cell differentiation, mutations in these key cytoskeleton components may change the physical/mechanical properties of the cells and determine the cell fate during cancer development. In particular, tumor microenvironment remodeling triggered by such alterations has been known to play important roles in autophagy, metabolism, cancer dormancy, and immune evasion. In this review paper, we will highlight the current understanding of how aberrant cytoskeleton networks affect cancer behaviors and cellular functions through mechanotransduction.

Phloretin in Benign Prostate Hyperplasia and Prostate Cancer: A Contemporary Systematic Review.

Currently, medication for benign prostate hyperplasia (BPH) and prostate cancer (PCa) are mainly based on modulating the hormone and nervous systems. However, side effects often affect patients, and might decrease their commitment to continuing the medication and lower their quality of life. Some studies have indicated that chronic inflammation might be the cause of BPH and PCa. Based on this hypothesis, the effect of phloretin, a potent anti-inflammatory and anti-oxidative flavonoid, has been researched since 2010. Results from animal and in-vitro studies, obtained from databases, also indicate that the use of phloretin in treating BPH and PCa is promising. Due to its effect on inflammatory cytokines, apoptosis or anti-apoptosis, reactive oxygen species, anti-oxidant enzymes and oxidative stress, phloretin is worthy of further study in human clinical trials regarding safety and effective dosages.

TNFRSF13B is a potential contributor to prostate cancer.

BACKGROUND: Immunodeficiencies are genetic diseases known to predispose an individual to cancer owing to defective immunity towards malignant cells. However, the link between immunodeficiency and prostate cancer progression remains unclear. Therefore, the aim of this study was to evaluate the effects of common genetic variants among eight immunodeficiency pathway-related genes on disease recurrence in prostate cancer patients treated with radical prostatectomy. METHODS: Genetic and bioinformatic analyses on 19 haplotype-tagging single-nucleotide polymorphisms in eight immunodeficiency pathway-related genes were conducted in 458 patients with prostate cancer after receiving radical prostatectomy. Furthermore, the TNFRSF13B was knocked down in 22Rv1 and PC-3 human prostate cancer cell lines via transfecting short hairpin RNAs and cell proliferation and colony formation assays were performed. The molecular mechanisms underlying the effects of TNFRSF13B were further explored by microarray gene expression profiling. RESULTS: TNFRSF13B rs4792800 was found to be significantly associated with biochemical recurrence even after adjustment for clinical predictors and false discovery rate correction (adjusted hazard ratio 1.78, 95% confidence interval 1.16-2.71, p = 0.008), and the G allele was associated with higher TNFRSF13B expression (p = 0.038). Increased TNFRSF13B expression suggested poor prognosis in four independent prostate cancer datasets. Furthermore, silencing TNFRSF13B expression resulted in decreased colony formation of 22Rv1 and PC-3 cells through modulating the cell cycle and p53 signalling pathways. CONCLUSIONS: The present study suggests the potential role of immunodeficiency pathway-related genes, primarily TNFRSF13B, in prostate cancer progression.

Disseminated peritoneal leiomyomatosis with malignant transformation involving right ureter: A case report.

BACKGROUND: Disseminated peritoneal leiomyomatosis (DPL) with myxoid leiomyosarcoma is a rare variant of leiomysosarcoma, and hematuria as a presenting symptom has never been reported. Through this case report, we emphasize the investigation of the etiology, clinical presentation, diagnosis, treatment, and prognosis of DPL with malignant changes mimicking metastatic urinary tract cancer and to help develop further clinical management. CASE SUMMARY: We describe a case of DPL with malignant transformation involving the right ureter after laparoscopic hysterectomy. An exploratory laparotomy was performed and all visible nodules were surgically removed. DPL with focal malignant transformation to myxoid leiomyosarcoma was confirmed based on pathology results. CONCLUSION: Professionals who preoperatively diagnose DPL with malignant change to myxoid leiomyosarcoma involving the genitourinary tract should consider symptoms of abdominal pain, hematuria, and imaging of disseminated pelvic tumors in women, especially those with prior history of laparoscopic hysterectomy. Early complete removal of all tumors is the cornerstone to prevent DPL from malignant changes.

Genetic Analysis Reveals the Prognostic Significance of the DNA Mismatch Repair Gene MSH2 in Advanced Prostate Cancer.

DNA damage repair is frequently dysregulated in advanced prostate cancer and has been linked to cancer susceptibility and survival outcomes. The aim of this study is to assess the influence of genetic variants in DNA damage repair pathways on the prognosis of prostate cancer. Specifically, 167 single nucleotide polymorphisms (SNPs) in 18 DNA damage repair pathway genes were assessed for association with cancer-specific survival (CSS), overall survival (OS), and progression-free survival (PFS) in a cohort of 630 patients with advanced prostate cancer receiving androgen deprivation therapy. Univariate analysis identified four SNPs associated with CSS, four with OS, and two with PFS. However, only MSH2 rs1400633 C > G showed a significant association upon multivariate analysis and multiple testing adjustments (hazard ratio = 0.75, 95% confidence interval = 0.63-0.90, p = 0.002). Furthermore, rs1400633 risk allele C increased MSH2 expression in the prostate and other tissues, which correlated with more aggressive prostate cancer characteristics. A meta-analysis of 31 gene expression datasets revealed significantly higher MSH2 expression in prostate cancer than in normal tissues (p < 0.001), and this high expression was associated with a poor prognosis of prostate cancer (p = 0.002). In summary, we identified MSH2 rs1400633 as an independent prognostic biomarker for prostate cancer survival, and the association of MSH2 with cancer progression lends relevance to our findings.

Modified Dual Docking Robotic Surgery for Hereditary Paraganglioma-Pheochromocytoma Syndrome.

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome is an uncommon genetic condition featured by an inherited predisposition to generate PGLs. Surgical resection of all tumors is the standard treatment for excess adrenaline production and tendency for metastasis. Nowadays, there are few case reports that have mentioned the surgical technique for hereditary PGL/PCC syndromes, especially robot-assisted surgery. Herein we present a rare case of hereditary PGL/PCC syndromes treated by partial cystectomy and right adrenalectomy at the same time with modified dual docking robotic surgical technique. Our dual docking robotic technique is a feasible option for patients with hereditary PGL/PCC syndromes of synchronous tumors in bladder and adrenal gland. It could not only prevent from second surgery but be safely performed without compromising disease control.

Novel approach to removing a steel bar extending from the scrotum to anterior abdominal wall: a case report.

Foreign body penetration from the scrotum is not rare. If a large and sharp foreign body pierces through an existing wound, it likely must be extended to improve exposure. Therefore, many traumatologists attempt to minimize the surgical wound caused by the removal of the foreign body. We describe a case of a foreign object penetrating from the scrotum to anterior abdominal wall. Our novel surgical approach is safe and feasible to use and provides minimal scarring, thereby allowing rapid recovery.

NRG1 Genetic Variant Influences the Efficacy of Androgen-Deprivation Therapy in Men with Prostate Cancer.

Neuregulins (NRGs) activate receptor tyrosine kinases of the ErbB family, and play essential roles in the proliferation, survival, and differentiation of normal and malignant tissue cells. We hypothesized that genetic variants of NRG signalling pathway genes may influence treatment outcomes in prostate cancer. To test this hypothesis, we performed a comprehensive analysis to evaluate the associations of 459 single-nucleotide polymorphisms in 19 NRG pathway genes with cancer-specific survival (CSS), overall survival (OS), and progression-free survival (PFS) in 630 patients with prostate cancer receiving androgen-deprivation therapy (ADT). After multivariate Cox regression and multiple testing correction, we found that NRG1 rs144160282 C > T is significantly associated with worsening CSS, OS, and PFS during ADT. Further analysis showed that low expression of NRG1 is closely related to prostate cancer, as indicated by a high Gleason score, an advanced stage, and a shorter PFS rate. Meta-analysis of 16 gene expression datasets of 1,081 prostate cancer samples and 294 adjacent normal samples indicate lower NRG1 expression in the former compared with the latter (p < 0.001). These results suggest that NRG1 rs144160282 might be a prognostic predictor of the efficacy of ADT. Further studies are required to confirm the significance of NRG1 as a biomarker and therapeutic target for prostate cancer.

Association between the polygenic liabilities for prostate cancer and breast cancer with biochemical recurrence after radical prostatectomy for localized prostate cancer.

Prostate and breast cancers are hormone-related malignancies and are characterized by a complex interplay of hundreds of susceptibility loci throughout the genome. Prostate cancer could be inhibited by eliminating androgens through castration or estrogen administration, thus facilitating long-term treatment of prostate cancer; however, the role of estrogen in prostate cancer remains unclear. This study aimed to determine whether polygenic risk scores (PRSs) comprising combinations of genome-wide susceptibility variants influence the clinical outcomes of prostate cancer patients. The study subjects were recruited from four medical centers in Taiwan, and genome-wide genotyping data were obtained from 643 prostate cancer patients. We derived the PRS for prostate cancer (PRS-PC) and for breast cancer (PRS-BC) for each patient. The association between the PRS-PC/PRS-BC at the age of prostate cancer onset and recurrence within seven years was evaluated using a regression model adjusted for population stratification components. A higher PRS-PC was associated with an earlier onset age for prostate cancer (beta in per SD increase in PRS = -0.89, P = 0.0008). In contrast, a higher PRS-BC was associated with an older onset age for prostate cancer (beta = 0.59, P = 0.02). PRS-PC was not associated with the risk of recurrence (hazard ratio = 1.03, P = 0.67), whereas a higher PRS-BC was associated with a low recurrence risk (hazard ratio = 0.86, P = 0.03). These results indicate that the genetic predisposition to breast cancer is associated with a low risk of prostate cancer recurrence. Further studies are warranted to explore the role of breast cancer susceptibility variants and estrogen signaling in prostate cancer progression.

PTBP1 Genetic Variants Affect the Clinical Response to Androgen-deprivation Therapy in Patients With Prostate Cancer.

BACKGROUND/AIM: Heterogeneous nuclear ribonucleoproteins (hnRNPs) contribute to multiple cellular functions including RNA splicing, stabilization, transcriptional and translational regulation, and signal transduction. However, the prognostic importance of genetic variants of hnRNP genes in clinical outcomes of prostate cancer remains to be elucidated. PATIENTS AND METHODS: We studied the association of 78 germline single-nucleotide polymorphisms (SNPs) in 23 hnRNP genes with the overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) in 630 patients with prostate cancer receiving androgen-deprivation therapy (ADT). RESULTS: PTBP1 rs10420407 was the most significant SNP (false discovery rate q=0.003) and carriers of the A allele exhibited poor OS, CSS, and PFS. Multivariate Cox analysis confirmed PTBP1 rs10420407 A allele was an independent negative prognostic factor for OS and PFS. Expression quantitative trait loci analysis showed that the rs10420407 A allele had a trend towards increased PTBP1 mRNA expression, and higher expression was correlated with prostate cancer aggressiveness and poor patient prognosis. Meta-analysis of 16 independent studies further indicated a tumorigenic effect of PTBP1, with a higher expression in prostate cancers than in adjacent normal tissues (p<0.001). CONCLUSION: Our data suggest that PTBP1 rs10420407 may influence patient response to ADT, and PTBP1 may be involved in the pathogenesis of prostate cancer progression.

Factors Predicting Oncological Outcomes of Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma in Taiwan.

BACKGROUND: Taiwan is one of the endemic regions where upper tract urothelial carcinoma (UTUC) accounts for approximately a third of all urothelial tumors. Owing to its high prevalence, extensive experience has been accumulated in minimally invasive radical nephroureterectomy (RNU). Although a variety of predictive factors have been explored in numerous studies, most of them were on a single-center or limited institutional basis and data from a domestic cohort are lacking. OBJECTIVE: This study aims to identify significant predicting factors of oncological outcomes, including overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and intravesical recurrence-free survival (IVRFS), following RNU for UTUC in Taiwan. METHODS: A multicenter registry database, Taiwan UTUC Collaboration Group, was utilized to analyze oncological outcomes of 3,333 patients undergoing RNU from 1988 to 2021 among various hospitals in Taiwan. Clinicopathological parameters were recorded according to the principles established by consensus meetings. The Kaplan-Meier estimator was utilized to estimate the survival rates, and the curves were compared using the stratified log-rank test. Univariate and multivariate analyses were performed with the Cox proportional hazard model to explore potential predicting factors. RESULTS: With a median follow-up of 41.8 months in 1,808 patients with complete information, the 5-year IVRFS, DFS, CSS, and OS probabilities were 66%, 72%, 81%, and 70%, respectively. In total, 482 patients experienced intravesical recurrence, 307 died of UTUC, and 583 died of any cause. Gender predominance was female (57%). A total of 1,531 patients (84.7%) had high-grade tumors; preoperative hydronephrosis presented in 1,094 patients (60.5%). Synchronous bladder UC was identified in 292 patients (16.2%). Minimally invasive procedures accounted for 78.8% of all surgeries, including 768 hand-assisted laparoscopic (42.5%) and 494 laparoscopic (27.3%) approaches. Synchronous bladder UC was the dominant adverse predicting factor for all survival outcomes. Other independent predicting factors for OS, CSS, and DFS included age ≧70, presence of preoperative hydronephrosis, positive surgical margin, LVI, pathological T and N staging, and laparoscopic RNU. CONCLUSION: Synchronous UC of the urinary bladder is an independent adverse prognostic factor for survival in UTUC. The presence of preoperative hydronephrosis was also corroborated as a disadvantageous prognostic factor. Our multivariate analysis suggested that laparoscopic RNU might provide better oncological control.

Comparing a new risk prediction model with prostate cancer risk calculator apps in a Taiwanese population.

PURPOSE: To develop a novel Taiwanese prostate cancer (PCa) risk model for predicting PCa, comparing its predictive performance with that of two well-established PCa risk calculator apps. METHODS: 1545 men undergoing prostate biopsies in a Taiwanese tertiary medical center between 2012 and 2019 were identified retrospectively. A five-fold cross-validated logistic regression risk model was created to calculate the probabilities of PCa and high-grade PCa (Gleason score â‰§ 7), to compare those of the Rotterdam and Coral apps. Discrimination was analyzed using the area under the receiver operator characteristic curve (AUC). Calibration was graphically evaluated with the goodness-of-fit test. Decision-curve analysis was performed for clinical utility. At different risk thresholds to biopsy, the proportion of biopsies saved versus low- and high-grade PCa missed were presented. RESULTS: Overall, 278/1309 (21.2%) patients were diagnosed with PCa, and 181 out of 278 (65.1%) patients had high-grade PCa. Both our model and the Rotterdam app demonstrated better discriminative ability than the Coral app for detection of PCa (AUC: 0.795 vs 0.792 vs 0.697, DeLong's method: P < 0.001) and high-grade PCa (AUC: 0.869 vs 0.873 vs 0.767, P < 0.001). Using a ≥ 10% risk threshold for high-grade PCa to biopsy, our model could save 67.2% of total biopsies; among these saved biopsies, only 3.4% high-grade PCa would be missed. CONCLUSION: Our new logistic regression model, similar to the Rotterdam app, outperformed the Coral app in the prediction of PCa and high-grade PCa. Additionally, our model could save unnecessary biopsies and avoid missing clinically significant PCa in the Taiwanese population.

Prostate Cancer Risk Calculator Apps in a Taiwanese Population Cohort: Validation Study.

BACKGROUND: Mobile health apps have emerged as useful tools for patients and clinicians alike, sharing health information or assisting in clinical decision-making. Prostate cancer (PCa) risk calculator mobile apps have been introduced to assess risks of PCa and high-grade PCa (Gleason score ≥7). The Rotterdam Prostate Cancer Risk Calculator and Coral-Prostate Cancer Nomogram Calculator apps were developed from the 2 most-studied PCa risk calculators, the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the North American Prostate Cancer Prevention Trial (PCPT) risk calculators, respectively. A systematic review has indicated that the Rotterdam and Coral apps perform best during the prebiopsy stage. However, the epidemiology of PCa varies among different populations, and therefore, the applicability of these apps in a Taiwanese population needs to be evaluated. This study is the first to validate the PCa risk calculator apps with both biopsy and prostatectomy cohorts in Taiwan. OBJECTIVE: The study's objective is to validate the PCa risk calculator apps using a Taiwanese cohort of patients. Additionally, we aim to utilize postprostatectomy pathology outcomes to assess the accuracy of both apps with regard to high-grade PCa. METHODS: All male patients who had undergone transrectal ultrasound prostate biopsies in a single Taiwanese tertiary medical center from 2012 to 2018 were identified retrospectively. The probabilities of PCa and high-grade PCa were calculated utilizing the Rotterdam and Coral apps, and compared with biopsy and prostatectomy results. Calibration was graphically evaluated with the Hosmer-Lemeshow goodness-of-fit test. Discrimination was analyzed utilizing the area under the receiver operating characteristic curve (AUC). Decision curve analysis was performed for clinical utility. RESULTS: Of 1134 patients, 246 (21.7%) were diagnosed with PCa; of these 246 patients, 155 (63%) had high-grade PCa, according to the biopsy results. After confirmation with prostatectomy pathological outcomes, 47.2% (25/53) of patients were upgraded to high-grade PCa, and 1.2% (1/84) of patients were downgraded to low-grade PCa. Only the Rotterdam app demonstrated good calibration for detecting high-grade PCa in the biopsy cohort. The discriminative ability for both PCa (AUC: 0.779 vs 0.687; DeLong's method: P<.001) and high-grade PCa (AUC: 0.862 vs 0.758; P<.001) was significantly better for the Rotterdam app. In the prostatectomy cohort, there was no significant difference between both apps (AUC: 0.857 vs 0.777; P=.128). CONCLUSIONS: The Rotterdam and Coral apps can be applied to the Taiwanese cohort with accuracy. The Rotterdam app outperformed the Coral app in the prediction of PCa and high-grade PCa. Despite the small size of the prostatectomy cohort, both apps, to some extent, demonstrated the predictive capacity for true high-grade PCa, confirmed by the whole prostate specimen. Following our external validation, the Rotterdam app might be a good alternative to help detect PCa and high-grade PCa for Taiwanese men.