Molecular Events Underlying Schistosomiasisrelated Bladder Cancer

Molecular events underlying urothelial neoplastic progression have identified alterations associated with specific genes along this pathway. Results collected from patient populations in North America, where transitional cell carcinomas (TCCs) predominate and multiple etiologic agents are implicated in progression, shows interesting findings: H-ras activation (59-61), p53 (62) and retinoblastoma gene (Rb) (63) inactivation and overexpression of the epidermal growth factor receptor (EGFR) (64) and C-erbB-2 (65). The prospective analysis of bladder tumors involving each of the genetic loci implicate p53 inactivation as a late event associated with the transition of tumor from a low-grade to a high-grade lesion (66). Loss of expression of the Rb gene product and overexpression of the EGFR are correlated with the invasive phenotype and along with p53 have been proposed as independent prognostic indicators of progression in bladder cancer. In contrast, H-ras activation has been consistently found to be represented in all grades of bladder tumors.

Ramchurren et al. (67) examined the molecular alterations reported in transitional cell carcinomas from Western countries in schistosomiasis-related squamous cell carcinomas of the bladder and whether genetic changes identified were indicative of the action of a specific etiologic agent. Preferential activation of the H-ras gene in approx 14% of the schistosomiasis-related squamous cell carcinoma lesions was demonstrated. No mutational events associated with codon hot spots in N- or K-ras genes were found using single strand conformation polymorphism (SSCP) analysis (67). In addition, the most common mutational event reported in transitional cell carcinoma, involving a G-T transversion at codon 12 resulting in a glycine-to-valine change (59,60,68), was not found in this group of schistosomiasis-related bladder cancers. Of the three ras activation events identified, two displayed codon-13 mutations, an occurrence recorded only rarely in transitional cell carcinoma.

Inactivation events associated with the p53 tumor suppressor gene are the most common molecular changes recorded in transitional cell carcinomas (62,69). Genetic changes associated with this locus are generally considered late events, possibly linked to transition from a low-grade to a high-grade transitional cell carcinoma (66). The frequency of detection of p53 alterations in bladder tumors has been reported in a range between 29% and 61% where such events have been shown to be indicative of a significantly lower progression-free interval (70). In the study by Ramchurren et al. (67), p53 inactivation was found in 57% tumors involving 23 point mutations and one deletion/insertion event. In addition, the preponderance of G-A transitions in the schis-tosomiasis cases harboring multiple mutations is also characteristic of the molecular changes elicited by the action of alkylating N-nitroso compounds. The p53 mutations found in schistosomiasis-bladder lesions are limited mainly to exons 7 and 8, with multiple mutations being a common occurrence. Therefore, p53 mutational events would be unlikely to occur as late events in schistosome-associated bladder squamous cell carcinomas and probably occur early on in bladder carcinogenesis. A study by Habuchi et al. (71) from Egypt showed p53 missense mutations involving exons 5, 6, 8, and 10. This may indicate the involvement of alternative carcinogenic cofactors in different schistosomiasis-infested regions.

The retinoblastoma gene product (Rb) is altered in bladder carcinoma cell lines and is an important prognostic variable in patients presenting with invasive bladder cancer (72,73). Altered patterns of Rb expression detected with immunocytochemistry are represented by undetectable or heterogeneous nuclear staining throughout tumor tissue and is considered indicative of more aggressive biologic behavior (72,73). Unlike the transitional cell carcinoma, which is characterized by Rb inactivation, Rb protein is expressed in a majority of invasive schistosomiasis-related squamous cell carcinoma of the bladder.

High-level expression of EGFRs is a common property of squamous cell carcinomas and occurs during the progression of normal epidermal cells to the malignant state (74). Many studies have described an association between increased expression of EGFR and high stage of bladder tumors (75). Ramchurren et al. (67) found strong immunoreaction for the EGFR in 67% of the schistosoma-associated bladder tumors. This finding is similar to the overexpression recorded in transitional cell carcinomas of the bladder reported in the Western population.

C-erbB-2, a member of the tyrosine-kinase-receptor family, encoding a transmembrane protein, is also amplified and/or overexpressed in bladder cancer (65). The findings are similar in schistosomiasis-associated bladder tumors, with strong immunostaining and frequent amplification and higher gene-copy number in high grade tumors (67).

In summary, the molecular changes occurring in schistosomal bladder carcinoma differ in several ways from those recorded in transitional cell carcinomas in the Western population.

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