الفهرس 
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Abstract
Bladder cancer is one of the peculiar Egyptian cancer pattern related to high prevalence of schistosomiasis. It accounts for 32.67% of all diagnosed cancers and it ranks the 1st among male cancer sites and the 5th among females. Bladder cancer is characterized by gender differential incidences and a recent change in the histological type.
Schistosomal associated bladder cancer has a specific histopathological classification. Transitional cell carcinoma is classified into: Papillary noninvasive carcinoma, papillary invasive carcinoma, and invasive transitional carcinoma.
Schistosomal infection and other factors lead to accumulation of genetic changes especially in cell-cycle genes and finally to transformation of urothelial cells.
p27 kip1 (p27) is a member of the universal cyclin-dependent kinase inhibitor (CDKI); family of cell-cycle regulators. The level of p27 protein expression decreases during tumor development and progression in some epithelial, lymphoid, and endocrine tissues. Decreasing of p27 protein level is associated with progression from superficial into invasive bladder cancer. Decreased p27 protein level is a negative prognostic indicator in human tumors including bladder cancer.
MDM2 is a protooncogene which encodes a nuclear transcription factor. MDM2 protein forms complexes with both wild type and mutant p53 protein and is involved in the autoregulatory feedback mechanism of p53. MDM2 is overexpressed in most cancers, with an overall frequency of gene amplification of 7% or overexpression of mRNA in bladder cancer, but both gene amplification and mRNA expression is elevated. For bladder carcinoma, MDM2 expression correlates with increased grade of tumors and was an indicator for future recurrence and increased in advanced stages of disease. MDM2 expression increases the risk of distant metastasis, contributing to the overall poorer prognosis for cancers expressing MDM2.
Since little is known about the added value of measuring of p27 and MDM2 in bladder cancer, the aim of this work was to examine the MDM2 and p27 gene expression biography in bladder cancer patients.
The current study included thirty patients (bilharzial and non bilharzial) with TCC bladder cancer without signs of distant metastasis, and ten patients with benign urologic diseases. Ten healthy volunteers of matched sex served as control group.
Voided random urine samples were collected under aseptic conditions and subjected to cytological examination. The number of exfoliated cells was counted directly using the hemocytometer.
The exfoliated cells were detected in controls [range: 2-10 (104); M ± SD: 4.42 ± 2.39 (104) cells/ml urine]. Exfoliation rate increased significantly (2.5 folds; p = 0.002*) in patients with urological benign diseases than controls. Exfoliation rate in TCC group increased significantly (5.9 folds; p = 0.000*) than controls and (2.4 folds; p = 0.000*) than urological benign diseases group. RNA extracted from exfoliated cells was also increased significantly (3.3 folds; p = 0.0002*) in patients with urological benign diseases and 9 folds in TCC group (p = 0.000*) than controls. There was also significant 2.8 folds increase in RNA amount in TCC than patients with urological benign diseases (p = 0.000*).
In addition, the current study showed that a significance association was observed between invasive histological type and schistsomal infestation (p = 0.008*), tumor size (p < 0.001*), and tumor growth pattern (p = 0.029*). Interestingly this is the first report regarding the association between invasive bladder cancer and schistsomal infestation. A significance association was observed between superficial histological type and tumor size (p = 0.013*).
Total RNA was extracted from exfoliated cells which are derived from basal cells; recent genetic damage to the basal layer of the bladder could be reflected in the presence of exfoliated cells. No prior study was conducted on assessing the gene expression of p27 and MDM2 in urothelial exfoliated cells.
The results of the present study revealed that the absence of p27 gene expression was significantly associated with both high tumor grade (exactly significant) and solid tumor growth pattern (p = 0.002*). Interestingly this is the first report regarding the association between loss of P27 and larger tumor size (p = 0.002*) and schistsomal infestation (p = 0.052*).
Similarly the acquisition of MDM2 gene expression significantly associated with both high tumor grade (exactly significant) and solid tumor growth pattern (p = 0.002*). Interestingly this is the first report regarding the association between acquisition of MDM2 and larger tumor size (p = 0.002*) and schistsomal infestation (p = 0.052*).
Tumor grade, size, multiplicity, growth pattern are well known to affect the outcome of urinary bladder carcinoma. Interestingly, schistsomal infestation significantly affected the disease-free survival in the current study. Overall survival significantly shortened with larger tumor size, tumor multiplicity, and solid tumor growth pattern.
In multivariate analysis, the tumor growth pattern was significant prognostic factor (p = 0.036) for disease-free and over-all survival while, high grade (exactly significant) and solid tumor growth pattern (relative risk 13.5; p = 0.023) were significant prognostic factors for the p27-/mdm2+ genetic pattern in TCC.
p27 or MDM2 would be useful as molecular markers in grading TCC. The potential for using cell cycle molecular markers with exfoliated urothelial cell RNA could establish an individualized fingerprinting as a method of surveillance for both tumor recurrence and progression as an adjunct to cystoscopy and cytology.