Association of GATA5 methylation with clinocopathological characteristics in non-muscle invasive bladder cancer / 동물의과학연구지

DNA methylation is the most common and well-characterized epigenetic change in human cancer. Recently, the association between GATA-binding protein 5 (GATA5) methylation and carcinogenesis of various types of tumors was investigated. The aim of the present study was to evaluate the effect of GATA5 methylation status on clinicopathological features and prognosis in primary non-muscle invasive bladder cancer (NMIBC) patients with a long-term followup period. The GATA5 methylation status was determined for 171 human bladder specimens (eight normal controls [NCs] and 163 primary NMIBC patients) using quantitative pyrosequencing analysis. The primary NMIBC tissues were obtained from patients who underwent transurethral resection (TUR) for histologically diagnosed transitional cell carcinomas between 1995 and 2012 at Chungbuk National University Hospital. GATA5 methylation was significantly higher in NMIBC patients than in NCs and was significantly associated with higher grade and more advanced stage of cancer. Kaplan-Meier estimates showed significant differences in tumor recurrence and progression according to GATA5 methylation status (each p<0.05). Our results show that increased methylation of GATA5 was significantly associated with not only aggressive characteristics but also poor prognosis in primary NMIBC patients. Alteration of GATA5 methylation might be used as a biomarker for prognosis of NMIBC patients. However, prospective and functional investigations are necessary to clarify the role of GATA5 methylation in future clinical management of patients with NMIBC.

Lower Levels of Human MOB3B Are Associated with Prostate Cancer Susceptibility and Aggressive Clinicopathological Characteristics

Mps one binder (MOB) proteins are integral components of signaling pathways that control important cellular processes, such as mitotic exit, centrosome duplication, apoptosis, and cell proliferation. However, the biochemical and cellular functions of the human MOB (hMOB) protein family remain largely unknown. The present study investigated the association between hMOB3B expression and clinicopathological characteristics of prostate cancer (PCa).Study subjects included 137 PCa patients and 137 age-matched benign prostatic hyperplasia (BPH) patients. hMOB3B expression was estimated using real-time PCR and compared with clinicopathological parameters of PCa. hMOB3B mRNA expression was significantly lower in PCa tissues than in BPH control tissues (P or =10 ng/mL), a Gleason score> or =8, and metastatic disease (any T, N+/M+) than in those with low PSA levels, a low Gleason score, and non-metastatic disease (each P<0.05). In conclusion, low levels of hMOB3B are closely associated with aggressive clinicopathologic features in patients with PCa. Our results suggest that hMOB3B may act as a tumor suppressor in human PCa.

Pyrosequencing Analysis of APC Methylation Level in Human Prostate Tissues: A Molecular Marker for Prostate Cancer

PURPOSE: Epigenetic alterations such as abnormal DNA methylation are associated with many human cancers. Differences in methylation patterns between neoplastic and normal cells can be used to detect cancer. The aim of the present study was to evaluate the effectiveness of detecting Adenomatous polyposis coli (APC) hypermethylation by quantitative pyrosequencing for discriminating between normal and prostate cancer (PCa) cells and for predicting tumor behaviors. MATERIALS AND METHODS: A total of 218 human prostate tissues obtained from our institute were assessed: 106 specimens of benign prostatic hyperplasia (BPH) and 112 specimens of PCa. The methylation status of APC was analyzed by quantitative pyrosequencing. The association between the APC methylation level and clinicopathological parameters was explored. RESULTS: The level of APC methylation was significantly higher in PCa specimens than in BPH specimens (33.3%+/-20.7% vs. 1.3%+/-1.8%, p<0.001). The sensitivity and specificity of APC methylation status in discriminating between PCa and BPH reached 89.3% and 98.1%, respectively. Similar results were obtained after stratification by stage, Gleason score, and prostate-specific antigen level. The APC methylation level correlated positively with Gleason score (p trend=0.016). There was no association between the APC methylation level and the PSA level or staging. CONCLUSIONS: Our results demonstrate that APC methylation is associated with PCa and its aggressive tumor features.

FAM70B as a Novel Prognostic Marker for Cancer Progression and Cancer-Specific Death in Muscle-Invasive Bladder Cancer

PURPOSE: To validate whether FAM70B, which was found in our micro-array profiling as a prognostic marker for cancer survival, could accurately predict prognosis in patients with muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: A total of 124 patients with MIBC were enrolled in this study. The FAM70B expression level was analyzed by real-time polymerase chain reaction by using RNA from tumor tissues. The prognostic effect of FAM70B was evaluated by Kaplan-Meier analysis and a multivariate Cox regression model. RESULTS: Kaplan-Meier estimates showed a significant difference in progression-free survival (log-rank test, p=0.011) and cancer-specific survival (log-rank test, p=0.017) according to FAM70B gene expression level. By multivariate Cox regression analysis, high FAM70B expression was predictive of cancer progression (hazard ratio [HR], 2.115, p=0.013) and cancer-specific death (HR, 1.925; p=0.033). In the subgroup analysis, high expression of FAM70B was associated with poor cancer-specific survival, progression-free survival, and overall survival in the patients who underwent cystectomy (log-rank test, p=0.013, p=0.036, p=0.005, respectively). In the chemotherapy group, FAM70B expression was associated with cancer-specific survival and progression-free survival (log-rank test, p=0.013, p=0.042, respectively). Moreover, high FAM70B expression was associated with shorter cancer-specific survival in localized or locally advanced tumor stages (log-rank test, p=0.016). CONCLUSIONS: We confirmed the significance of FAM70B as a prognostic marker in a validation cohort. Therefore, we propose that the FAM70B gene could be used to more precisely predict cancer progression and cancer-specific death in patients with MIBC.

DNA Methylation of GSTP1 in Human Prostate Tissues: Pyrosequencing Analysis

PURPOSE: DNA methylation is an important epigenetic mechanism of gene regulation and plays essential roles in tumor initiation and progression. Differences in methylation patterns between neoplastic and normal cells can be used to detect the presence of cancer. The aim of the present study was to evaluate the usefulness of glutathione-S-transferase-Pi (GSTP1) hypermethylation in discriminating between normal and prostate cancer (PCa) cells and in predicting tumor characteristics by use of quantitative pyrosequencing analysis. MATERIALS AND METHODS: A total of 100 human prostate tissues obtained from our institute were used in this study: 45 for benign prostatic hyperplasia (BPH) and 55 for PCa. The methylation level of GSTP1 was examined by a quantitative pyrosequencing analysis. The associations between GSTP1 methylation level and clinico-pathological parameter were also compared. RESULTS: The level of GSTP1 methylation was significantly higher in PCa samples than in BPH samples (56.7+/-32.7% vs. 1.6+/-2.2%, p<0.001). The sensitivity and specificity of GSTP1 methylation status in discriminating between PCa and BPH reached 85.5% and 100%, respectively. Even after stratification by stage, Gleason score, and prostate-specific antigen (PSA) level, similar results were obtained. A positive correlation between GSTP1 methylation level and serum PSA level was observed (r=0.303, p=0.002). There were no associations between GSTP1 methylation level and age, Gleason score, and staging. CONCLUSIONS: Our study demonstrates that GSTP1 methylation is associated with the presence of PCa and PSA levels. This methylation marker is a potentially useful indicator for the detection and monitoring of PCa.

mRNA Expression of S100A8 as a Prognostic Marker for Progression of Non-Muscle-Invasive Bladder Cancer

PURPOSE: S100A8 is a member of the S100 protein family containing 2EF-hand calcium-binding motifs. S100 proteins are involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. Altered expression of this protein is associated with various diseases and cancers. The present study aimed to evaluate whether S100A8 has prognostic value for non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: A total of 103 primary NMIBC samples obtained by transurethral resection were evaluated. mRNA levels were examined by real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. The results were compared with clinico-pathological parameters. The Kaplan-Meier method was applied to plot the curves for progression-free survival. The multivariate Cox regression model was used to identify the independent prognostic factors for progression. RESULTS: mRNA expression levels of S100A8 were significantly related to the progression of NMIBC. Kaplan-Meier estimates demonstrated significant differences in tumor progression according to the level of S100A8 expression (log-rank test, p<0.001). The multivariate Cox regression model revealed that the S100A8 mRNA expression level (hazard ratio: 12.538; 95% confidence interval: 2.245-70.023, p=0.004) was an independent predictor for disease progression of NMIBC. CONCLUSIONS: Expression levels of S100A8 might be a useful prognostic marker for disease progression of NMIBC.