Deletions of p15 and p16 in schistosomal bladder cancer correlate with transforming growth factor-α expression

Objectives: Cell proliferation is stimulated by growth factors and inhibited by p15 and p16 gene products. We compared cell regulators, TGF-α, p15, and p16, in schistosomal and non-schistosomal bladder cancer to explore possible differences in their alterations between the two subtypes and their correlations with proliferation pattern [synthetic phase fraction (SPF)], DNA ploidy, and clinicopathological factors. Methods: Tumor tissue samples were obtained from 120 patients. Expressions of p15 and p16 genes were investigated by the polymerase chain reaction, while TGF-α protein expression was measured by an enzyme immunoassay (EIA) method. Results: Deletion of both p15 and p16 was observed in 62 and 46 bladder tumors, respectively. TGF-α was overexpressed in 64 bladder tumors. A highly significant association was observed between the two deleted genes and TGF-α positivity. Of the entire group, p15 and p16 alteration and positive TGF-α (≥cutoff value) were significantly expressed in schistosomal bladder cancer (68.1%, 60.9%, and 65.2%), and squamous cell carcinoma type (SCC) (69.1%, 64.7% and 72.1%) compared to those with non-schistosomal bladder cancer (29.4%, 7.8%, and 37.3%) or transitional cell carcinoma (TCC) (28.8%, 3.8%, and 28.8), respectively. A significant association between p15 and p16 deletion and TGF-α positivity with high SPF, aneuploid DNA pattern, late stages, and high histological grades was also documented. Conclusion: Alteration of p15 and p16 genes and overexpression of TGF-α appears to be an event in bladder cancer that occurs more frequently in schistosomal bladder cancer and SCC, and may play an important role in their development. These observations may provide insight into treatment guided by molecular changes