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.

Potential Linkage between High Normalized Electromechanical Activation Time (EMAT), an Early Systolic Time Interval Abnormality with Metabolic Syndrome.

BACKGROUND: High electromechanical activation time (EMAT) is associated with paroxysmal atrial fibrillation and heart failure. Little is known about the association between EMAT and metabolic syndrome (MetS), a precursor of cardiovascular disease. OBJECTIVES: To explore the association between EMAT and MetS. METHODS: A total of 429 male volunteers were divided into MetS (n = 135, age 60.3 ± 3.7 years) and non-MetS (n = 294, age 58.1 ± 26.6 years) groups in this cross-sectional study. A complete medical history, fasting blood analysis and phonoelectrocardiographic parameters were recorded. EMAT was defined as the time from the onset of Q- wave to the peak first heart sound (Q-S1 interval), and this interval divided by the R-R interval for heart rate correction was calculated as normalized EMAT (nEMAT). RESULTS: The subjects with MetS had a significantly higher rate of positive nEMAT (nEMAT ≥ 15%: 6.7% vs. 2%, p = 0.015), higher heart rate (HR, 71.9 ± 12.0 vs. 69.2 ± 11.1 bpm, p = 0.022) but shorter left ventricular ejection time (LVST = 312.4 ± 33.5 vs. 319.8 ± 31.8 msec, p = 0.029). However, the normalized LVST (nLVST) was not significantly different after adjusting for HR. In multivariate analysis, nEMAT was significantly associated with MetS (odds ratio = 3.43, 95% confidence interval = 1.195-9.837, p = 0.022). CONCLUSIONS: Positive nEMAT, a prolonged early phase of contraction, was significantly associated with MetS in males. High nEMAT may be an earlier sign of cardiac function abnormality in MetS.

Genetic variants in the circadian rhythm pathway as indicators of prostate cancer progression.

BACKGROUND: To determine the association between circadian pathway genetic variants and the risk of prostate cancer progression. METHODS: We systematically evaluated 79 germline variants in nine circadian pathway genes in a cohort of 458 patients with localized prostate cancer as the discovery phase. We then replicated the significant findings in another cohort of 324 men with more advanced disease. The association of each variant with prostate cancer progression was evaluated by a log-rank test and Cox regression. RESULTS: A single nucleotide polymorphism of the neuronal PAS domain protein 2 (NPAS2) gene (rs6542993 A>T) was found to be associated with a significantly higher risk of disease progression in both localized (P = 0.001) and advanced (P = 0.039) prostate cancer cases. In silico analysis revealed decreased expression levels of NPAS2 in carriers of the T allele of rs6542993 compared with those carrying the A allele. Consistently, downregulation of NPAS2 expression was associated with more aggressive prostate cancer and poor progression-free survival (log-rank P = 0.002). CONCLUSIONS: The NPAS2 rs6542993 polymorphism may be a promising biomarker, and may shed light on the pathways that govern prostate cancer progression.

A Rare Delayed Bladder Migration of a Hem-o-lok Clip 5 Years after Robotic-Assisted Radical Prostatectomy.

Bladder migration of a Hem-o-lok® clip, due to robotic-assisted radical prostatectomy (RARP), is uncommon, and would form a foreign body in the bladder and present as lower urinary tract symptoms after the early postoperative period. We hereby report a rare, delayed appearance of a secondary bladder stone due to the migration of a Hem-o-lok® clip that occurred 5 years after RARP.

Hepatocyte Nuclear Factor-4α P2 Promoter Variants Are Associated With the Risk of Metabolic Syndrome and Testosterone Deficiency in Aging Taiwanese Men.

BACKGROUND: Hepatocyte nuclear factor-4α (HNF4A) can influence the risk of insulin resistance that is postulated to be an important link between metabolic syndrome (MetS) and testosterone deficiency (TD) in men. AIM: To investigate the relationship between single-nucleotide polymorphisms (SNPs) of HNF4A and the risk of developing MetS and TD in a population of aging Taiwanese men. METHODS: A free health screening of men over 40 years of age was conducted in a medical center in Kaohsiung City, Taiwan. All participants underwent a physical examination, answered a questionnaire on demographics and medical history, completed the Androgen Deficiency in The Aging Male questionnaire to assess clinical symptoms of TD, and provided 20-mL whole blood samples for biochemical, hormonal, and genetic evaluation. MAIN OUTCOME MEASURE: 3 common SNPs (rs11574736, rs1884613, and rs2144908) of HNF4A were selected and identified using a TaqMan 5' allelic discrimination assay. RESULTS: 559 men were enrolled for this study (mean age, 55.8± 4.9 years). Prevalence of TD was significantly higher (P = .031) in subjects with MetS (16.8%) than those without MetS (10.1%). In SNP rs1884613 of HNF4A, subjects with the C allele carried a 1.31- and 1.50-times higher risk of developing MetS and TD, respectively, compared to those with the G allele, after adjusting for potential covariates. In addition, subjects with the CC genotype were exposed to a 1.91- and 2.20-times higher risk of developing MetS and TD, respectively, compared to those with the GG genotype. CLINICAL IMPLICATIONS: Our findings may point to the importance of the role played by insulin resistance in the link between MetS and TD. STRENGTH & LIMITATIONS: Our current work is the first report with adequate sample size to evaluate the role of genetic variants of HNF4A on the risk of both MetS and TD in men. The limitations included subjects enrolled from a free health screening and single measurement of serum testosterone levels. CONCLUSION: The rs1884613 SNP marker of HNF4A is significantly associated with an increased risk for developing both MetS and TD in aging Taiwanese men. Further population-based studies utilizing larger samples of different ethnicities may be needed to confirm these preliminary results. Liu C-C, Lee Y-C, Hung S-P. Hepatocyte Nuclear Factor-4α P2 Promoter Variants Are Associated With the Risk of Metabolic Syndrome and Testosterone Deficiency in Aging Taiwanese Men. J Sex Med 2018;15:1527-1536.

Cancer Stem Cell Gene Variants Predict Disease Recurrence in Patients Treated with Radical Prostatectomy for Prostate Cancer.

Background: Cancer stem cells (CSCs) are involved in tumor progression and drug resistance. We hypothesized that variants in CSC marker genes influence treatment outcomes in prostate cancer. Methods: Ten potentially functional single nucleotide polymorphisms (SNPs) in seven prostate CSC marker genes, TACSTD2, PROM1, ITGA2, POU5F1, EZH2, PSCA, and CD44, were selected for analysis of their association with disease recurrence by Kaplan-Meier analysis and Cox regression in a cohort of 320 patients with localized prostate cancer receiving radical prostatectomy. Results: We identified one independent SNP, rs2394882, in POU5F1 that was associated with prostate cancer recurrence (hazard ratio 0.32, 95% confidence interval 0.14-0.71, P = 0.005) after adjustment for known clinical predictors. Further in silico functional analyses revealed that rs2394882 affects POU5F1 expression, which in turn is significantly correlated with prostate cancer aggressiveness and patient prognosis. Conclusion: Our results suggest that rs2394882 is prognostically relevant in prostate cancer, possibly by modulating the expression of the CSC gene POU5F1.

Prognostic Value of Prostaglandin-endoperoxide Synthase 2 Polymorphisms in Prostate Cancer Recurrence after Radical Prostatectomy.

UNLABELLED: Backgroud: Increasing evidence suggests the involvement of chronic inflammation in the progression of prostate cancer, and prostaglandin-endoperoxide synthase 2 (PTGS2), also known as cyclooxygenase-2, catalyzes the rate-limiting steps of the pathway. We hypothesized that genetic variants of PTGS2 can influence the outcome of prostate cancer patients. METHODS: We genotyped five haplotype-tagging single-nucleotide polymorphisms (SNPs) to detect common genetic variations across the PTGS2 region in 458 prostate cancer patients treated with radical prostatectomy. RESULTS: One SNP, rs4648302, was associated with disease recurrence. Five-year recurrence-free survival rate increased according to the number of variant alleles inherited (55.6%, 70.7%, and 100.0% for patients with different genotypes; P = 0.037), and the effect was maintained in multivariable analysis. Public dataset analyses also suggested that PTGS2 expression was correlated with prostate cancer prognosis. CONCLUSION: Our results indicated that PTGS2 could be a potential prognostic marker to improve the prediction of disease recurrence in prostate cancer patients.

CYBA as a Potential Biomarker for Renal Cell Carcinoma: Evidence from an Integrated Genetic Analysis.

BACKGROUND/AIM: Oxidative stress plays an important role in various pathogenic processes, and disruption in the coordinated production of NADPH oxidase (NOX)-derived reactive oxygen species has been associated with carcinogenesis. However, little is known about whether genetic variants in NOX can contribute to the development of renal cell carcinoma (RCC). PATIENTS AND METHODS: This study aimed to bridge this knowledge gap by analysing the association of 10 single-nucleotide polymorphisms in the phagocyte NOX genes, CYBA and CYBB, with RCC risk and tumour characteristics in 630 RCC patients and controls. Differential gene expression and patient prognosis analyses were performed using gene expression data obtained from public databases. RESULTS: Multivariate analysis and multiple testing corrections revealed the A allele of rs7195830 in CYBA to be a significant risk allele for RCC, compared to the G allele [odds ratio (OR)=1.70, 95% confidence interval (CI)=1.27-2.26, p<0.001]. A pooled analysis of 17 renal cancer gene expression datasets revealed a higher CYBA expression in RCC than in normal tissues. Moreover, high CYBA expression was associated with advanced tumour characteristics and worse patient prognosis. CONCLUSION: CYBA might play an oncogenic role in RCC and serve as a predictive indicator of patient prognosis.

Metabolic dysfunction-associated fatty liver disease is an early predictor for testosterone deficiency in aging men without metabolic syndrome.

Background and aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a valuable marker for identifying individuals at increased risk of metabolic dysfunction, liver-related complications, and cardiovascular disease. However, the association between MAFLD and testosterone deficiency (TD) in aging men remains poorly understood. This study aimed to investigate the association between MAFLD and the risk of TD in aging Taiwanese men, with a specific focus on those without metabolic syndrome (MetS). Methods: A free health screening program was conducted for Taiwanese men aged over 40 years in Kaohsiung, Taiwan. Participants underwent physical examinations, completed questionnaires regarding demographics, medical history, and clinical symptoms of TD, and provided 20-mL whole blood samples for biochemical, adipocytokine, and hormonal evaluations. Fatty liver index was used to evaluate the risk of fatty liver. Diagnostic criteria for MAFLD included fatty liver along with overweight/obesity, type 2 diabetes, or evidence of metabolic dysregulation. Results: A total of 631 men (mean age: 54.4 ± 8.4 years) were enrolled. The prevalence rates of TD and MetS were significantly higher in men with MAFLD compared to those without (both p < 0.001). Additionally, the presence of MAFLD showed a significant correlation with adipocytokines associated with insulin resistance, such as adiponectin, leptin, and retinol-binding protein-4 (RBP-4) levels (all p < 0.001). Among men without MetS, those with MAFLD had a 3.89- and 4.74-fold higher risk of total testosterone < 300 ng/dL and TD, respectively, after adjusting for potential covariates. Conclusion: MAFLD is associated with an elevated risk of TD in aging Taiwanese men, particularly in the absence of MetS. This finding suggests that MAFLD could serve as an early predictor of TD, facilitating the identification of high-risk individuals and enabling timely interventions. Further research is needed to validate these findings and explore the underlying mechanisms linking MAFLD, TD, and MetS in diverse populations.

Anticancer Effects of Morusin in Prostate Cancer via Inhibition of Akt/mTOR Signaling Pathway.

Prostate cancer (PCa) is the second most prevalent cancer in men worldwide. The majority of PCa incidences eventually progress to castration-resistant PCa (CRPC), thereby establishing an urgent need for new effective therapeutic strategies. This study aims to examine the effects of morusin, a prenylated flavonoid isolated from Morus alba L., on PCa progression and identify the regulatory mechanism of morusin. Cell growth, cell migration and invasion, and the expression of EMT markers were examined. Cycle progression and cell apoptosis were examined using flow cytometry and a TUNEL assay, while transcriptome analysis was performed using RNA-seq with results being further validated using real-time PCR and western blot. A xenograft PCa model was used to examine tumor growth. Our experimental results indicated that morusin significantly attenuated the growth of PC-3 and 22Rv1 human PCa cells; moreover, morusin significantly suppressed TGF-[Formula: see text]-induced cell migration and invasion and inhibited EMT in PC-3 and 22Rv1 cells. Significantly, morusin treatment caused cell cycle arrest at the G2/M phase and induced cell apoptosis in PC-3 and 22Rv1 cells. Morusin also attenuated tumor growth in a xenograft murine model. The results of RNA-seq indicated that morusin regulated PCa cells through the Akt/mTOR signaling pathway, while our western blot results confirmed that morusin suppressed phosphorylation of AKT, mTOR, p70S6K, and downregulation of the expression of Raptor and Rictor in vitro and in vivo. These results suggest that morusin has antitumor activities on regulating PCa progression, including migration, invasion, and formation of metastasis, and might be a potential drug for CRPC treatment.

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.

Identification of a Steroid Hormone-Associated Gene Signature Predicting the Prognosis of Prostate Cancer through an Integrative Bioinformatics Analysis.

The importance of anti-androgen therapy for prostate cancer (PC) has been well recognized. However, the mechanisms underlying prostate cancer resistance to anti-androgens are not completely understood. Therefore, identifying pharmacological targets in driving the development of castration-resistant PC is necessary. In the present study, we sought to identify core genes in regulating steroid hormone pathways and associating them with the disease progression of PC. The selection of steroid hormone-associated genes was identified from functional databases, including gene ontology, KEGG, and Reactome. The gene expression profiles and relevant clinical information of patients with PC were obtained from TCGA and used to examine the genes associated with steroid hormone. The machine-learning algorithm was performed for key feature selection and signature construction. With the integrative bioinformatics analysis, an eight-gene signature, including CA2, CYP2E1, HSD17B, SSTR3, SULT1E1, TUBB3, UCN, and UGT2B7 was established. Patients with higher expression of this gene signature had worse progression-free interval in both univariate and multivariate cox models adjusted for clinical variables. The expression of the gene signatures also showed the aggressiveness consistently in two external cohorts, PCS and PAM50. Our findings demonstrated a validated eight-gene signature could successfully predict PC prognosis and regulate the steroid hormone pathway.

Protodioscin inhibits bladder cancer cell migration and growth, and promotes apoptosis through activating JNK and p38 signaling pathways.

Bladder cancer is one of the most common malignancies of the male genitourinary urinary system. Protodioscin is a steroidal saponin with anti-cancer effects on several types of cancers; however, the anti-cancer activities of protodioscin on bladder cancer have not yet been investigated. Therefore, we aimed to examine the anti-cancer effects of protodioscin on bladder cancer. Two types of bladder cancer cell lines, non-muscle-invasive 5637 cells and muscle-invasive T24 cells, were used to evaluate the effects of protodioscin on cell growth, migration, invasion and epithelial-mesenchymal transition(EMT) marker expressions. Transcriptome analysis was performed by RNA-seq and validated using real-time PCR and western blot; additionally, an in vivo xenograft animal model was established and the anti-tumor effects of protodioscin were tested. Our results demonstrated that protodioscin inhibited cell proliferation, migration, motility and invasion on 5637 and T24 cells. Additionally, protodioscin also induced cell apoptosis and arrested the progression of cell cycle at G2 phase in bladder cancer cells. Moreover, protodioscin inhibited EMT through increased protein expression of E-cadherin and decreased protein expression of N-cadherin and vimentin. RNA-seq analysis indicated that protodioscin regulated mitogen-activated protein kinase(MAPK) and phosphoinositide 3-kinases(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR) signaling pathways as further verified by Western blot. Furthermore, protodioscin significantly inhibited tumor growth in vivo. Our results indicated that protodioscin inhibits cell growth, migration and invasion and induces apoptosis and G2 phase cell cycle arrest by activated p38 and JNK signaling pathways in bladder cancer cells, suggesting that protodioscin could be an effective agent for bladder cancer treatment.

Novel insights into the anti-cancer effects of 3-bromopyruvic acid against castration-resistant prostate cancer.

3-bromopyruvic acid (3-BP), a small molecule alkylating agent, has been emerged as a glycolytic inhibitor with anticancer activities. However, the effects of 3-BP on the growth and metastasis in prostate cancer have not been well investigated. Here we investigated the anti-cancer effects of 3-BP on prostate cancer in vitro and in vivo. Cell growth, apoptosis, migration, motility, and invasion were examined. The tumor growth ability was determined using a xenograft murine model. Transcriptome analysis using RNA-seq was performed to explore the mechanism of action of 3-BP. Our experimental results showed that 3-BP effectively inhibits prostate cancer cell growth, especially in castration-resistant prostate cancer (CRPC) cells. Moreover, 3-BP induces apoptosis and suppresses cell migration, motility, epithelial-mesenchymal transition (EMT), and invasion in CRPC cells. In addition, 3-BP also attenuates tumor growth in a xenograft murine model. Through transcriptome analysis using RNA-seq, 3-BP significantly regulates the cell cycle pathway and decreases the expression of downstream cycle cycle-associated genes in CRPC cells. The results of cell cycle analysis indicated that 3-BP arrests cell cycle progression at G2/M in CRPC cells. These results suggest that 3-BP has the potential in inhibiting CRPC progression and might be a promising drug for CRPC treatment.

Fatty liver index is associated with the risk of testosterone deficiency in aging men without metabolic syndrome.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is suggested to be a precursor of metabolic syndrome (MetS) and could influence the risk of testosterone deficiency (TD). Fatty liver index (FLI) is a simple and useful screening tool for NAFLD. We determined the association between the risk of NAFLD assessed by FLI and TD in aging Taiwanese men, especially those without MetS. MATERIALS AND METHODS: A free health screening program was conducted for men (age: >40 years) in a medical center in Kaohsiung, Taiwan. All participants underwent a physical examination; answered a questionnaire assessing demographics, medical history, and clinical symptoms of TD; and provided 20-mL whole blood samples for biochemical, adipocytokine, and hormonal evaluations. The risk of NAFLD was evaluated using FLI. The presence of NAFLD was ruled out if FLI value was <25 and ruled in if FLI value was ≥35. RESULTS: A total of 552 men (mean age: 54.7 ± 7.7 years) were enrolled. The prevalence rates of TD and MetS were significantly higher among men with NAFLD than those without NAFLD (both p < 0.001). FLI was significantly correlated with total testosterone (TT) and adipocytokines associated with insulin resistance, such as adiponectin, leptin, and retinol-binding protein-4 (RBP-4) levels, respectively (all p < 0.001). Among men without MetS, those at risk of and with NAFLD had a 3.82 and 8.50 times higher risk of TD, respectively, than those without NAFLD after adjusting for potential covariates. CONCLUSION: The FLI is associated with the risk of TD in aging Taiwanese men, especially in those without MetS. Our findings also suggest that insulin resistance may be an important link among the inter-relationships of NAFLD, MetS, and TD. Further population-based studies with larger sample sizes of different ethnicities are warranted to confirm these preliminary results.

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.

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.

Genetic Association Analysis of Cell Cycle Regulators Reveals YWHAZ Has Prognostic Significance in Prostate Cancer.

BACKGROUND/AIM: This study aimed to identify the genes that cause biochemical recurrence (BCR) following radical prostatectomy (RP) in men with localized prostate cancer. PATIENTS AND METHODS: A two-stage genetic association study of 19 single-nucleotide polymorphisms in 11 key cell cycle regulation genes was carried out. BCR-free survival after RP was evaluated in a discovery cohort of 458 patients with prostate cancer, and replication was investigated in another cohort of 185 patients. RESULTS: A consistent association was found between BCR and rs2290291 (discovery: p=0.008; replication: p=0.029). rs2290291 is located in the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), and was predicted to possess a regulatory function that affected YWHAZ expression. Furthermore, YWHAZ expression was frequently up-regulated in advanced tumours, and associated with poorer survival in patients with prostate cancer. CONCLUSION: YWHAZ rs2290291 was found to be associated with BCR. YWHAZ may function as a putative oncogene during prostate cancer progression.

Genetic association analysis identifies a role for ANO5 in prostate cancer progression.

Anoctamins were originally identified as a family of calcium-activated chloride channels, but recently their roles in the development of different types of malignancies were suggested. Here, we evaluated the associations between 211 common single-nucleotide polymorphisms in 10 anoctamin genes with biochemical recurrence (BCR) after radical prostatectomy (RP) for localized prostate cancer. Four SNPs (ANO4 rs585335, ANO5 rs4622263, ANO7 rs62187431, and ANO10 rs118005571) remained significantly associated with BCR after multiple test correction (P < .05 and q = 0.232) and adjustment for known prognostic factors. Expression quantitative trait loci analysis found that ANO5 rs4622263 C and ANO10 rs118005571 C alleles were associated with decreased mRNA expression levels. Moreover, lower expression of ANO5 was correlated with more advanced tumors and poorer outcomes in two independent prostate cancer cohorts. Taken together, ANO5 rs4622263 was associated with BCR, and ANO5 gene expression was correlated with patient prognosis, suggesting a pivotal role for ANO5 in prostate cancer progression.

Interrelationship of environmental melamine exposure, biomarkers of oxidative stress and early kidney injury.

Melamine contamination has remained pervasive in the environment even after the 2008 toxic milk scandal. Exposure to chronic low dosages of melamine is known to induce renal tubular damage, increasing the risk of stone formation and early kidney injury. This damage may come about via increased oxidative stress, but no studies of this possibility have been performed in humans. We conducted two human studies in 80 workers from melamine tableware factories (melamine workers) and 309 adult patients with calcium urolithiasis (stone patients) to evaluate the relationships between urinary melamine levels and two urinary biomarkers of oxidative stress, 8-oxo-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA). Both human studies showed urinary melamine levels to be significantly and positively correlated with urinary 8-OHdG and MDA, indicating melamine exposure can increase oxidative stress. Additionally, we used structure equation modeling to evaluate relative contribution of type of melamine-induced oxidative stress on renal tubular injury and found that MDA mediated 36 %-53 % of the total effect of melamine on a biomarker of renal tubular injury, N-Acetyl-ß-d Glucosaminidase (NAG). In conclusion, our findings suggest exposure to low-dose melamine can increase oxidative stress and increase the risk of early damage to kidneys in humans.