Molecular and kinetic features of transitional cell carcinomas of the bladder: biological and clinical implications

Abstract

Molecular and kinetic analyses have contributed to our understanding of the biology of transitional cell carcinomas (TCC) of the bladder. The concordant pattern of X-chromosome inactivation of multiple TCCs appearing at different times and at different sites and concordant genetic abnormalities in a subset of muscle-invasive TCC strongly support a monoclonal origin and a homogeneous tumor cell selection throughout the neoplasm. However, topographic intratumor heterogeneity results from the accumulation of genetic lesions in tumor suppressor genes, predominantly neurofibromatosis (NF)-1-defective in the superficial compartment and tumor protein p53 (TP53)-defective in the deep one, with lower proliferation and down-regulation of apoptosis in the latter. TCCs follow the general concept of multistep carcinogenesis and proceed through two distinct genetic pathways responsible for generating different TCC morphologies. These are the inactivation of cyclin-dependent kinase inhibitors (p15, p16, and p21WAF/CIP1) in low-grade TCC and early TP53-mediated abnormalities in high-grade TCC. TCC progression correlates with genetic instability and accumulation of collaborative genetic lesions mainly involving TP53, retinoblastoma (RB)-1, and growth factors. Distinctive genetic (low incidence of RB-1 and NF-1 abnormalities) and kinetic (slower cell turnover) profiles also correlate with a "single-file" infiltration pattern and poor survival in muscle-invasive TCCs. The underlying molecular changes of carcinoma in situ involve multiple and more extensive deletions (normally TP53-defective) than coexistent invasive TCC, suggesting an independent genetic evolution, while low-grade dysplasia is mainly polyclonal and shows a low rate of gene deletions.

Preneoplastic non-papillary lesions and conditions of the urinary bladder: an update based on the Ancona International Consultation

“…With the use of image analysis subtle morphological nuclear abnormalities that are not readily seen by the human eyes have been 4 demonstrated in urinary bladders harboring preneoplastic and neoplastic lesions. Recent studies showed that 50% of the histologically normal urothelium adjacent to superficial urothelial carcinoma has genetic anomalies on chromosome 9, similar to the anomalies found in the coexistent carcinoma [4,5]. In addition, non-diploid histograms occur in 4.2-53.5% of normal-looking urothelium adjacent to bladder tumors (L. Andersson, personal communication).…”

Expression Patterns of Cyclins D1, E and Cyclin-Dependent Kinase Inhibitors p21(Waf1/Cip1) and p27(Kip1) in Urothelial Carcinoma: Correlation with Other Cell-Cycle-Related Proteins (Rb, p53, Ki-67 and PCNA) and Clinicopathological Features

“…Alterations of Rb gene have been observed in several epithelial tumours suggesting that structural abnormalities, including mutations and/or deletions of the Rb gene, may result in the inactivation of tumour suppressor protein and may be involved in tumorigenesis [45]. Although conflicting results of pRb expression in bladder cancer have been shown by some investigators, they found an important prognostic expressing variable [46][47][48]. In the present study we have found no relationship between cyclin D1 overexpression and the loss of Rb protein suggested the non-existence of an Rb-cyclin D1 pathway.…”

Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi

“…19,20 However, the association of multiple genetic alterations would become statistically less probable as the number of molecular markers increases and is useful to test clonal expansions in tumors. 7,18 Although genetic abnormalities are probably asymmetrically acquired, there is a correlation with tumor cell topography in both luminal and solid organs, 1,[19][20][21][22][23] which has not been assessed in skin melanocytic lesions. Any potential topographic segregation of tumor cells will influence interpretations of the results, supporting a linear model if progressive grading is parallel to intraepithelial-to-invasive topography of tumor cells.…”