Large-scale analysis of cell cycle regulators in urothelial bladder cancer identifies p16 and p27 as potentially useful prognostic markers

AIMS: We investigated the value of multiple cell cycle markers for their prognostic impact on overall survival and recurrence-free survival in urothelial carcinoma (UC). METHODS: A tissue microarray consisting of 99 UCs was evaluated for the expression of p53, p16, p21, p27, cyclin D1, cyclin E , Bcl-2, Ki-67 and PCNA. Statistical analysis was performed applying Kaplan-Meier and Cox regression models using receiver operator characteristic curves for determination of markers' cutoffs. RESULTS: Expression above the cutoffs of Ki-67, p53 and p27, particularly in high-grade and early-stage UC, was associated with worse overall survival, while expression of p16 indicated a better outcome in low-grade and low-stage tumors. Recurrence-free survival was better in patients with high-grade UC expressing PCNA, p16 and cyclin E, and low-grade UC expressing Bcl-2 above the cutoffs, but worse in all tumors with high Ki-67. CONCLUSION: Cell cycle deregulation in UC is complex and the prognostic value of the various involved proteins should be differentially regarded with respect to this complexity and other tumor characteristics such as grade and stage. Our results point towards the role of p16- and p27-associated pathways in tumor progression and indicate that, by using standardized approaches for tissue antigen expression, evaluation and cutoff determination, single potentially useful prognostic markers could be identified

Biomarkers of exposure and effect—interpretation in human risk assessment

The effect of exposure to carcinogenic polycyclic aromatic hydrocarbons adsorbed onto respirable air particles (PM2.5, diameter < 2.5 μm) on DNA adducts and chromosomal aberrations was repeatedly studied in Prague, Czech Republic, in groups of policemen working in the downtown area and in bus drivers. Personal exposure was evaluated using personal samplers during working shifts. DNA adducts were analyzed in lymphocytes by the 32P-postlabeling assay and chromosomal aberrations were analyzed by conventional cytogenetic analysis and fluorescent in situ hybridization (FISH). The impact of environmental pollution on DNA adducts and chromosomal aberrations was studied in a total of 950 subjects. Our results suggest that the environmental exposure of nonsmokers to concentrations higher than 1 ng benzo[a]pyrene/m3 represents a risk of DNA damage, as indicated by an increase in DNA adducts and the genomic frequency of translocations determined by FISH

Expression analysis of imbalanced genes in prostate carcinoma using tissue microarrays

To identify candidate genes relevant for prostate tumour prognosis and progression, we performed an exhaustive gene search in seven previously described genomic-profiling studies of 161 prostate tumours, and four expression profiling studies of 61 tumours. From the resulting list of candidate genes, six were selected for protein-expression analysis based on the availability of antibodies applicable to paraffinised tissue: fatty acid synthase (FASN), MYC, β-adrenergic receptor kinase 1 (BARK1, GRK2) the catalytic subunits of protein phosphatases PP1α (PPP1CA) and PP2A (PPP2CB) and metastasis suppressor NM23-H1. These candidates were analysed by immunohistochemistry (IHC) on a tissue microarray containing 651 cores of primary prostate cancer samples and benign prostatic hyperplasias (BPH) from 175 patients. In univariate analysis, expression of PP1α (P=0.001) was found to strongly correlate with Gleason score. MYC immunostaining negatively correlated with both pT-stage and Gleason score (P<0.001 each) in univariate as well as in multivariate analysis. Furthermore, a subgroup of patients with high Gleason scores was characterised by a complete loss of BARK1 protein (P=0.023). In conclusion, our study revealed novel molecular markers of potential diagnostic and therapeutic relevance for prostate carcinoma

EpCAM is predominantly expressed in high grade and advanced stage urothelial carcinoma of the bladder

BACKGROUND: EpCAM is an adhesion molecule of the basolateral membranes in a variety of epithelial cells. Over-expression has been detected in many epithelial tumours and has been associated with high stage, high grade and a worse survival in some tumour types. AIMS: To assess the prognostic value of EpCAM in urothelial carcinoma of the bladder. METHODS: EpCAM expression was analysed by immunohistochemistry using a monoclonal antibody (clone VU-1D9) on a tissue microarray comprising 99 urothelial carcinomas of the bladder diagnosed between 1994 and 1997. RESULTS: A significant relationship between high grade, advanced stage, and EpCAM expression was found, and expression of EpCAM was associated with a worse overall survival when compared to EpCAM negative tumours (p = 0.033). Multivariate analysis showed that EpCAM expression was not an independent prognostic factor for overall survival in urothelial carcinoma of the bladder. CONCLUSION: EpCAM expression is associated with advanced stage, high grade and poor overall survival in urothelial carcinoma of the bladder, but lacks an independent prognostic significance. The strong association with high grade tumours suggests a possible role during tumour progression and makes EpCAM a potential target for antibody mediated therapy

Prognostic significance of tenascin-C expression in superficial and invasive bladder cancer

Aims: Tenascin-C (Tn-C) is an extracellular matrix glycoprotein that is upregulated in malignant tumours. Tn-C promotes cell growth, cell migration, and angiogenesis. It has been suggested to be a prognostic factor in various types of malignant tumours, but there is little information on its significance in bladder cancer with regard to overall survival (OS) and recurrence free survival (RFS). Methods: Tn-C expression was studied in 106 patients with bladder cancer diagnosed between 1994 and 1997. Immunohistochemistry was performed using a monoclonal antibody against Tn-C. RFS and OS were estimated by the Kaplan–Meier method and compared by the log rank test in univariate analysis and by the Cox multistep regression method in multivariate analysis. Results: Within the mean follow up period of 126 months, patients with diffuse Tn-C staining in the tumour stroma had a significantly worse OS than those with negative staining or only moderate Tn-C expression (p  =  0.025). Patients with cytoplasmic expression of Tn-C had a significantly better OS than those without (p  =  0.001). Multivariate analysis, taking into consideration age, grade, stage, tumour associated carcinoma in situ, progression, and Tn-C staining in tumour stroma, showed that only expression of Tn-C in invasive tumour cells was an independent positive prognostic factor for OS (p  =  0.049). Conclusions: Tn-C may provide important prognostic information in bladder cancer depending on the expression pattern in the tumour stroma or cytoplasm of the tumour cells